Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them

ABSTRACT

A compound selected from the group consisting of a compound of the formulawherein A is selected from the group consisting ofand the other substituents are defined in the specification having an inhibitory activity of NO-synthase enzymes producing nitrogen mono-oxide and/or an activity which traps the reactive oxygen species.

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/381,749 filed Sep. 22, 1999 which is a 371 of PCT/FR98/00288filed Feb. 16, 1998.

A subject of the present invention is new derivatives of2-(iminomethyl)amino-phenyl which have an inhibitory activity onNO-synthase enzymes producing nitrogen monoxide NO and/or an activitywhich traps the reactive oxygen species (ROS). The invention relates tothe derivatives corresponding to general formula (I) defined below,their preparation methods, the pharmaceutical preparations containingthem and their use for therapeutic purposes, in particular their use asNO-synthase inhibitors and selective or non selective traps for reactiveoxygen species.

Given the potential role of NO and the ROS's in physiopathology, the newderivatives described corresponding to general formula (I) may producebeneficial or favourable effects in the treatment of pathologies wherethese chemical species are involved. In particular:

cardiovascular and cerebro-vascular disorders including for exampleartherosclerosis, migraine, arterial hypertension, septic shock,ischemic or hemorragic cardiac or cerebral infarctions, notably thoserelated with complications of coronary artery bypass grafting, ischemiasand thromboses.

disorders of the central or peripheral nervous system such as forexample neurodegenerative diseases where there can in particular bementioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing,senile dementias including Alzheimer's disease, Huntington's chorea,Parkinson's disease, Creutzfeld Jacob disease and prion diseases,amyotrophic lateral sclerosis but also pain, cerebral and bone marrowtraumas, addiction to opiates, alcohol and addictive substances,erective and reproductive disorders, cognitive disorders,encephalopathies, encephalopathies of viral or toxic origin.

disorders of the skeletal muscle and neuromuscular joints (myopathy,myosis) as well as cutaneous diseases.

proliferative and inflammatory diseases such as for exampleartherosclerosis, pulmonary hypertension, respiratory distress,glomerulonephritis, portal hypertension, psoriasis, arthrosis andrheumatoid arthritis, fibroses, amyloidoses, inflammations of thegastro-intestinal system (colitis, Crohn's disease) or of the pulmonarysystem and airways (asthma, sinusitis, rhinitis).

organ transplants.

auto-immune and viral diseases such as for example lupus, AIDS,parasitic and viral infections, diabetes, multiple sclerosis.

cancer.

neurological diseases associated with intoxications (Cadmium poisoning,inhalation of n-hexane, pesticides, herbicides), associated withtreatments (radiotherapy) or disorders of genetic origin (Wilson'sdisease).

all the pathologies characterized by an excessive production ordysfunction of NO and/or ROS's.

In all these pathologies, there is experimental evidence demonstratingthe involvement of NO or ROS's (J. Med. Chem. (1995) 38, 4343-4362; FreeRadic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3,327-333).

Furthermore, NO Synthase inhibitors, their use and more recently thecombination of these inhibitors with products having antioxidant orantiradicular properties have already been described in previous Patents(respectively U.S. Pat. Nos. 5,081,148; 5,360,925 and an unpublishedPatent Application).

A subject of the present invention is the derivatives of2-(iminomethyl)amino-phenyl, their preparation and their therapeuticuse.

The compounds of the invention correspond to general formula (I):

in which:

A represents a hydrogen atom or:

either a

 radical in which R₁ and R₂ represent, independently, a hydrogen atom, ahalogen, the OH group, a linear or branched alkyl or alkoxy radicalhaving from 1 to 6 carbon atoms,

R₃ represents a hydrogen atom, a linear or branched alkyl radical havingfrom 1 to 6 carbon atoms or a —COR₄ radical,

R₄ represents a linear or branched alkyl radical having from 1 to 6carbon atoms,

or a

 radical in which R₃ represents a hydrogen atom, a linear or branchedalkyl radical having from 1 to 6 carbon atoms or a —COR₄ radical, R₄represents a linear or branched alkyl radical having from 1 to 6 carbonatoms,

or a

 radical in which R₅ represents a hydrogen atom, the OH group or alinear or branched alkyl or alkoxy radical having from 1 to 6 carbonatoms;

B represents a linear or branched alkyl radical having from 1 to 6carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and in particularthe thiophene, furan, pyrrole or thiazole radicals, the aryl radicalbeing optionally substituted by one or more groups chosen from thelinear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6carbon atoms;

X represents —Z₁—, —Z₁—CO—, —CH═, —CH═CH—CO—, —Z₁—NR₃—CO—Z′₁—,—CO—NR₃—Z′₁—, —Z₁—NR₃—CS—, —Z₁—NR₃—SO₂— or a single bond;

Het does not exist or represents a heterocycle containing from 1 to 5heteroatoms chosen from O, N, S which can be substitued by one or moresubstituents X′—OR₃, X′—NR₃, X′—S—R₃ and such as for example: oxetane,pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoine, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine or4-aminopiperidine;

Y represents a radical chosen from the —Z₂—Q—, —Z₂—CO—, —Z₂—NH—CO—,—Z₂—CH₂—NR₃—CO—, —NR₃—Z₂—Q—, —NR₃—CO—Z₂—Q—, —NR₃—NH—CO—Z₂—, —NH—NH—Z₂—,—NR₃—O—Z₂—, —NR₃—SO₂—NR₃—Z₂—, —O—Z₂—Q—, —O—CO—Z₂—Q— or —S—Z₂—Q—radicals, in which Q represents a single bond, O—Z₃, R₃—N—Z₃ or S—Z₃;

Z₁, Z′₁, Z₂ and Z₃ represent independently a single bond or a linear orbranched alkylene radical having from 1 to 6 carbon atoms; preferably,Z₁, Z′₁, Z₂ and Z₃ represent —(CH₂)_(m)—, m being an integer comprisedbetween 0 and 6;

R₆ represents a hydrogen atom or an OH group;

it being understood that when Het is absent, then A is not a hydrogenatom and that when A is hydrogen then Het does not represent apiperidine, pyrrolidine or morpholine radical;

or are salts of the latter.

The compounds of general formula (I) containing an asymmetrical centreare of isomeric form. The racemic and enantiomeric forms of thesecompounds also form part of this invention.

The compounds of the invention can exist in the state of bases or ofaddition salts in particular with organic or inorganic acids or withbases, and in particular in the state of hydrates, hydrochlorides,dihydrochlorides, fumarates or hemifumarates.

By linear or branched alkyl having from 1 to 6 carbon atoms is meant inparticular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexylradicals. By linear or branched alkoxy having from 1 to 6 carbon atomsis meant radicals the alkyl radical of which has the meaning indicatedpreviously. By halogen is meant fluorine, chlorine, bromine or iodineatoms.

Preferably, the compounds of general formula (I) are such that theyinclude at least one of the following features:

A represents a

radical in which R₁ and R₂ represent, independently, a branched alkylradical having from 3 to 6 carbon atoms,

R₃ represents a hydrogen atom, a linear or branched alkyl radical havingfrom 1 to 6 carbon atoms or a —COR₄ radical,

R₄ represents a linear or branched alkyl radical having from 1 to 6carbon atoms,

or A represents a

 radical in which R₃ represents a hydrogen atom or a linear or branchedalkyl radical having from 1 to 6 carbon atoms;

B represents a thiophene or phenyl radical;

X represents —Z₁—CO— or —CO—NR₃—Z′₁;

Het is absent or represents a piperazine or tetrahydropyridinyl radical;

Y represents —Z₂—Q— or —NR₃—Z₂—Q—;

R₆ represents a hydrogen atom.

A particular subject of the invention is the following compounds ofgeneral formula (I), described in the examples (in the form of salts incertain cases):

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

3,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;

4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;

N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;

N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;

N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;

N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-urea;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thiourea;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-urea;

N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;

N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamide;

(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

N-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinyl)phenyl}-2-thiophene-carboximidamide;

2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide;

N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;

N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;

N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamide;

N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;

N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;

N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;

N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide;

N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furancarboxamide;

3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2-imidazolidinedione;

2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinone;

5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione;

2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamide;

5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridinecarboxamide;

N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidinecarboxamide;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl-4-thiazolecarboxamide;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamide;

methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylate;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine;

3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine;

4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamine;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamide;

1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinone;

3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamide;

4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamine;

4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamine;

3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole;

1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;

1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidine;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidine;

as well as their salts, in particular their hydrochlorides,dihydrochlorides, fumarates or hemi-fumarates.

In a preferential manner, the compounds according to the invention willbe one of the following compounds:

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;

3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;

N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;

N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;

N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;

N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}-carbonylamino}-urea;

or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

Other preferred compounds for the invention will be the followingcompounds:

4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;

3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;

or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

Particularly preferred compounds of the invention will be as follows:

N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidaimide;

N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;

or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

More particularly preferred compounds of the invention will be asfollows:

N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

The invention also offers useful new synthesis intermediates of generalformula (Σ)

in which:

A, X, Het, Y and R₆ have the same meaning as in general formula (I); and

W represents an amino or nitro radical;

with the exception however of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide.

The invention further comprises a process for preparing a compound ofgeneral formula (I) as defined earlier, characterized in that a compoundof general formula (Σ)

in which:

A, X, Het, Y and R₆ have the same meaning as in general formula (I); and

W represents an amino radical;

is reacted in a lower alcohol, such as methanol, ethanol, isopropylalcohol or t-butanol, preferably in isopropyl alcohol, at a temperaturebetween 20 and 90° C., for example at 50° C., and for one to 48 hours,preferably for 15 to 24 hours, optionally in the presence of DMF, with acompound of general formula (IV)

 said compound of general formula (IV) being optionally salified by amineral acid G, B having the same meaning as in general formula (I) andL representing a leaving group and in particular an alkoxy, thioalkyl,sulphonic acid, halide, aryl alcohol or tosyl radical (other leavinggroups well known to a person skilled in the art which can optionally beused for the invention are described in the following work: AdvancedOrganic Chemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315).Preferably, G represents HCl, HBr or HI.

According to a particular variant of the invention, the compounds of theinvention correspond to general formula (I)_(L):

in which:

A represents:

either a

 radical in which R₁ and R₂ represent, independently, a hydrogen atom, ahalogen, the OH group, a linear or branched alkyl or alkoxy radicalhaving from 1 to 6 carbon atoms,

R₃ represents a hydrogen atom, a linear or branched alkyl radical havingfrom 1 to 6 carbon atoms or a —COR₄ radical,

R₄ represents a linear or branched alkyl radical having from 1 to 6carbon atoms,

or a

 radical in which R₃ has the meaning indicated above

or a

 radical in which R₅ represents a hydrogen atom, the OH group or alinear or branched alkyl or alkoxy radical having from 1 to 6 carbonatoms;

B represents a linear or branched alkyl radical having from 1 to 6carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and in particularthe thiophene, furan, pyrrole or thiazole radicals, the aryl radicalbeing optionally substituted by one or more groups chosen from thelinear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6carbon atoms;

X represents —Z₁—, —Z₁—CO—, —CH═CH—CO—, —Z₁—NR₃—CO—, —Z₁—NR₃—CS—,—Z₁—NR₃—SO₂— or a single bond;

Y represents a radical chosen from the —Z₂—Q, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine,4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—CO—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—, —NR₃—SO₂—NR₃—Z₂—, —O—Z₂—Q—, —O—CO—Z₂—Q— or—S—Z₂—Q— radicals, in which Q represents a single bond, O—Z₃, R₃—N—Z₃ orS—Z₃;

Z₁, Z₂ and Z₃ represent independently a single bond or a linear orbranched alkylene radical having from 1 to 6 carbon atoms; preferably,Z₁, Z₂ and Z₃ represent —(CH₂)_(m)—, m being an integer comprisedbetween 0 and 6;

R₆ represents a hydrogen atom or an OH group;

or are salts of the latter.

There will generally be preferred the compounds of general formula(I)_(L) for which:

X represents a linear or branched alkylene radical having from 1 to 6carbon atoms and Y represents a piperazine, homopiperazine,2-methylpipërazine, 2,5-dimethylpiperazine, 4-aminopiperidine,—NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—, —NH—NH—Z₂— or —NR₃—O—Z₂— radical; or

X represents —Z₁—CO— or —CH═CH—CO— and Y represents a piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine,4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—, —NH—NH—Z₂—, —NR₃—O—Z₂—,—O—Z₂—Q— radical or —NR₃—CO—Q′— radical with Q′=R₃—N—Z₃; or

X represents —Z₁—NR₃—CO— and Y represents —Z₂—Q—, —NH—Z₂—Q—,—NH—CO—Z₂—Q″— with Q″=O—Z₃—, R₃—N—Z₃— or S—Z₃—, or Y represents—NR₃—SO₂—NR₃—Z₂— or —O—Z₂—Q—; or

X represents —Z₁—NH—CO— and Y represents a piperazine, homopiperazine,2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine,—NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—, —NH—NH—Z₂— or —NR₃—O—Z₂— radical; or

X represents —Z₁—NR₃—SO₂— and Y represents —Z₂—Q″— with Q″=O—Z₃—,R₃—N—Z₃— or S—Z₃—, or Y represents —NR₃—Z₂—Q—; or

X represents —Z₁— and Y represents —O—CO—Z₂—Q—; or

X represents —Z₁—NR₃—CS— and Y represents —NH—Z₂—Q—, or a piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine,4-aminopiperidine, —NR₃—Z₂—Q—, —NH—NH—Z₂— or —NR₃—O—Z₂— radical; or

X represents a bond and Y represents —O—Z₂—NH—, —S—Z₂—NH—.

Moreover, the X-Y group will preferably be chosen from the followingradicals:

in which T represents a single bond, the —NR₃— radical or the —CO—NR₃—radical, or

in which R_(p) represents a hydrogen atom or a methyl radical, or

in which U represents a —Z₂, —NR₃—CO—, —CO—Z₂—O—, —CO—, —NR₃— radical oran oxygen atom, or

the Z₁, Z₂ and R₃ radicals having the meaning indicated above.

Finally, there will be particularly preferred for the invention thecompounds of general formula (I)_(L) presenting the followingcharacteristics:

either:

A represents:

X represents —CO— or —NH—CO—;

and Y represents an —NH—Z₂—Q— or piperazine radical, Q representing asingle bond or an O—Z₃, R₃—N—Z₃ or S—Z₃ radical, and Z₂ and Z₃representing independently a bond or a linear or branched alkyleneradical having from 1 to 6 carbon atoms and R₃ represents a hydrogenatom or a linear or branched alkyl radical having from 1 to 6 carbonatoms.

or: R₆ is an OH group.

The invention also offers, as new industrial products, the syntheticintermediates of the products of general formula (I)_(L), namely theproducts of general formula (II)_(L):

in which:

W represents an amino or nitro radical,

A represents:

either a

radical in which R₁ and R₂ represent, independently, a hydrogen atom, ahalogen, the OH group, a linear or branched alkyl or alkoxy radicalhaving from 1 to 6 carbon atoms,

R₃ represents a hydrogen atom, a linear or branched alkyl radical havingfrom 1 to 6 carbon atoms or a —COR₄ radical,

R₄ representing a linear or branched alkyl radical having from 1 to 6carbon atoms,

or a

 radical in which R₃ has the meaning indicated above

or a

 radical in which R₅ represents a hydrogen atom, the OH group or alinear or branched alkyl or alkoxy radical having from 1 to 6 carbonatoms;

X represents —Z₁—, —Z₁—CO—, —CH═CH—CO—, —Z₁—NR₃—CO—, —Z₁—NR₃—CS—,—Z₁—NR₃—SO₂— or a single bond;

Y represents a radical chosen from the —Z₂—Q, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine,4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—CO—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—, —NR₃—SO₂—NR₃—Z₂—, —O—Z₂—Q—, —O—CO—Z₂—Q— or—S—Z₂—Q— radicals, in which Q represents a single bond, O—Z₃, R₃—N—Z₃ orS—Z₃;

Z₁, Z₂ and Z₃ represent independently a single bond or a linear orbranched alkylene radical having from 1 to 6 carbon atoms; preferably,Z₁, Z₂ and Z₃ represent —(CH₂)_(m)—, m being an integer comprisedbetween 0 and 6;

R₆ represents a hydrogen atom or an OH group;

with the exception however of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide;

or the salts of the latter.

Moreover, the invention offers in particular, as new industrialproducts, the following compounds, which are synthetic intermediates ofproducts of general formula (I):

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamide;

4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide;

4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol;

2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenol;

2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-methyl}-phenol;

2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-methyl}-phenol;

2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol;

2,6-dimethoxy-4-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-phenol;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamide;

3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine;

1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine;

2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-nitrophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;

2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-urea;

N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide;

3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide;

3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide;

3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamide;

5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;

5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)-carbonylamino]-urea;

N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-thiourea;

N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[2-(4-nitrophenyl)ethyl]-urea;

N-[2-(4-aminophenyl)ethyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-nitrophenyl)piperazine;

1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-aminophenyl)piperazine;

hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;

1-(4-aminophenyl)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepine;

hydrochloride duN-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamidehydrochloride;

(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-}4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)ethyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-aminophenyl)ethyl]-benzamide;

2-(4-nitrophenyl)ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate;

2-(4-aminophenyl)ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

or their salts.

Finally, this particular variant of the invention also comprisesprocesses for the preparation of compounds of general formula (I)_(L) asdefined above and consisting, for example, of the reaction in a loweralcohol such as methanol, ethanol, isopropyl alcohol or t-butanol,preferably in isopropyl alcohol, at a temperature comprised between 20and 90° C., for example at 50° C., and for 1 to 48 hours, preferably for15 to 24 hours, optionally in the presence of DMF, of a compound ofgeneral formula (III)_(L) as defined above with a compound of generalformula (IV)_(L)

said compound of general formula (IV)_(L) being optionally salified by amineral acid G, B having the meaning indicated above and L representinga leaving group and in particular an alkoxy, thioalkyl, sulphonic acid,halide, aryl alcohol or tosyl radical (other leaving groups well knownto a person skilled in the art which can optionally be used for theinvention are described in the following work: Advanced OrganicChemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315).Preferably, G represents HCl, HBr or HI.

Other production processes can be envisaged and can be consulted in theliterature (for example: The Chemistry of amidines and imidates, Vol. 2,Saul PATAI and Zvi RAPPOPORT, John Wiley & Sons, 1991).

According to another particular variant of the invention, the compoundsof the invention correspond to general formula (I)_(H):

in which:

A is a hydrogen atom or an aromatic corresponding to structures:

in which R₁ and R₂ represent, independently, a hydrogen atom, a halogen,the OH group, a linear or branched alkyl radical having from 1 to 6carbon atoms, a linear or branched alkoxy radical having from 1 to 6carbon atoms

R₃ represents a hydrogen atom, a linear or branched alkyl radical havingfrom 1 to 6 carbon atoms or a —COR₄ radical, R₄ representing an alkylradical having from 1 to 6 carbon atoms, or

B represents a linear or branched alkyl radical having from 1 to 6carbon atoms, phenyl, pyridinyl or a heterocycle with 5 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and moreparticularly: thiophene, furan, pyrrole or thiazole, the carbons ofwhich are optionally substituted by one or more groups chosen from alinear or branched alkyl radical having from 1 to 6 carbon atoms; analkoxy radical having from 1 to 6 carbon atoms or a halogen;

X represents —CO—N(R₃)—X′—, —NH—CO—X′—, —CH═, —CO— or a bond, X′representing —(CH₂)_(n)— with n an integer from 0 to 6;

Y represents —Y′—, —CO—NH—Y′, —Y′—NH—CO—, —CO—Y′—, —Y′—CO, —N(R₃)—Y′—,—Y′—N(R₃)—, Y′—CH₂—N(R₃)—CO—, —O—Y′—, —Y′—O—, —S—Y′—, —Y′—S—, —Y′—O—Y′—,—Y′—N(R₃)—Y′— or a bond, Y′ representing —(CH₂)_(n)— with n an integerfrom 0 to 6;

Het represents a heterocycle containing from 1 to 5 heteroatoms chosenfrom O, N, S which can be substitued by one or more substituents X′—OR₃,X′—NR₃, X′—S—R₃ and such as for example:

oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoine, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,

with the exception of the following heterocycles: piperazines,homopiperazines, 4-aminopiperidine;

it being understood that when A represents a hydrogen atom, Het does notrepresent a piperidine, pyrrolidine or morpholine radical.

The compounds of general formula (I)_(H) containing one or moreasymmetrical centres having isomer forms. The racemics and enantiomersof these compounds are also part of this invention. Similarly, thecompounds of the invention can also exist in the state of bases oraddition salts with acids.

More particularly the invention relates to the compounds of generalformula (I)_(H) in which:

A is a hydrogen atom or an aromatic corresponding to the structure:

in which R₁ and R₂ represent, independently a linear or branched alkylradical having 1 to 6 carbon atoms or a linear or branched alkoxyradical having from 1 to 6 carbon atoms, R₃ represents a hydrogen atomor a linear or branched alkyl radical having from 1 to 6 carbon atoms;

B represents a heterocycle with 5 members containing from 1 to 4heteroatoms chosen from O, S, N and more particularly: thiophene, furan,pyrrole or thiazole, the carbons of which are optionally substitued byone or more groups chosen from a linear or branched alkyl having from 1to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms ora halogen;

X represents —NH—CO—X′—, —CH═, —CO— or a bond, X′ representing—(CH₂)_(n)— with n an integer from 0 to 6;

Y represents —Y′—, —Y′—NH—CO—, —Y′—CO—, —Y′—O—, —Y′—O—Y′—, —Y′—N(R₃)—Y′—or a bond, Y′ representing —(CH₂)_(n)— with n an integer from 0 to 6;

Het represents a heterocycle containing from 1 to 5 heteroatoms chosenfrom O, N, S which can be substituted by one or more substituentsX′—OR₃, X′—NR₃, X′—S—R₃ and such as for example:

oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,

with the exception of the following heterocycles: piperazines,homopiperazines, 4-aminopiperidine.

Quite particularly the invention relates to the compounds of generalformula (I)_(H) in which:

A is a hydrogen atom or an aromatic corresponding to the structure:

 in which:

R₁ and R₂ represent, independently a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms or a linear or branched alkoxy radicalhaving from 1 to 6 carbon atoms,

R₃ represents a hydrogen atom or a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms;

B represents a thiophene ring, the carbons of which are optionallysubstituted by one or more groups chosen from a linear or branched alkylhaving from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6carbon atoms or a halogen;

X represents —NH—CO—X′—, —CH═, —CO— or a bond, X′ representing—(CH₂)_(n)— with n an integer from 0 to 6;

Y represents —Y′—, —Y′—NH—CO—, —Y′—CO—, —Y′—O—, —Y′—O—Y′—, —Y′—N(R₃)—Y′—or a bond, Y′ representing —(CH₂)_(n)— with n an integer from 0 to 6;

Het represents a heterocycle containing from 1 to 5 heteroatoms chosenfrom O, N, S which can be substituted by one or more substituentsX′—OR₃, X′—NR₃, X′—S—R₃ and such as for example:

oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,

with the exception of the following heterocycles: piperazines,homopiperazines, 4-aminopiperidine.

Preferred compounds for this variant of the invention include thefollowing compounds (described in the examples):

N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide;

N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;

N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;

N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamide;

N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;

N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;

N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;

N-(4-}[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide;

N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furancarboxamide;

3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedione;

2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinone;

5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione;

2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamide;

5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridinecarboxamide;

N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidinecarboxamide;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}4-thiazolecarboxamide;

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamide;

methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylate;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine;

3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine;

4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamine;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamide;

1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinone;

3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamide;

4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamine;

4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamine;

3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole;

1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;

1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidine;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidine;

as well as their salts, in particular their hydrochlorides,dihydrochlorides, fumarates or hemi-fumarates.

Preferred compounds for this variant of the invention are the followingcompounds:

N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide hydroiodide;

N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;

N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamidefumarate;

N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamidehydrochloride;

N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;

N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamidehydroiodide;

N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamidefumarate

N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;

N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamidefumarate;

N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furancarboxamide hydroiodide;

3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedionehydrochloride;

2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-l{imino(2-thienyl)-methylamino]phenyl]-4-thiazolidinonehydrochloride;

5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedionefumarate;

2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamidehydrochloride;

5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridinecarboxamide hydrochloride;

N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidinecarboxamide fumarate;

N-[4-(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl)phenyl]-2-thiophenecarboximidamidehydroiodide;

N-[4-hydroxy-3,5-bis-(1,1-dimethyl)ethyl-phenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamide hydrochloride;

or their salts or enantiomers.

N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamideor its salts is the most preferred compound among the compounds of thisvariant of the invention.

The invention also offers, as new industrial products, the syntheticintermediates of the products of general formula (I)_(H), namely theproducts of general formula (II)_(H), (III)_(H), (V)_(H), (VI)_(H) and(VII)_(H)

in which

A is a hydrogen atom or an aromatic corresponding to structures:

 in which:

R₁ and R₂ represent, independently, a hydrogen atom, a halogen, the OHgroup, a linear or branched alkyl radical having from 1 to 6 carbonatoms, a linear or branched alkoxy radical having from 1 to 6 carbonatoms,

R₃ represents a hydrogen atom, a linear or branched alkyl radical havingfrom 1 to 6 carbon atoms or a —COR₄ radical R₄ representing an alkylradical having from 1 to 6 carbon atoms,

B represents a linear or branched alkyl radical having from 1 to 6carbon atoms, phenyl, pyridinyl or a heterocycle with 5 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and moreparticularly: thiophene, furan, pyrrole or thiazole, the carbons ofwhich are optionally substituted by one or more groups chosen from alinear or branched alkyl having from 1 to 6 carbon atoms, an alkoxyradical having from 1 to 6 carbon atoms or a halogen;

X represents —CO—N(R₃)—X′—, —NH—CO—X′—, —CH═, —CO— or a bond, X′representing —(CH₂)_(n)— with n an integer from 0 to 6;

Y represents —Y′—, —CO—NH—Y′, —Y′—NH—CO—, —CO—Y′—, —Y′—CO, —N(R₃)—Y′—,—Y′—N(R₃)—, Y′—CH₂—N(R₃)—CO—, —O—Y′—, —Y′—O—, —S—Y′—, —Y′—S—, —Y′—O—Y′—,—Y′—N(R₃)—Y′— or a bond, Y′ representing —(CH₂)_(n)— with n an integerfrom 0 to 6;

Het represents a heterocycle containing from 1 to 5 heteroatoms chosenfrom O, N, S which can be substituted by one or more substituentsX′—OR₃, X′—NR₃, X′—S—R₃ and such as for example:

oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,

with the exception of the following heterocycles: piperazines,homopiperazines, 4-aminopiperidine;

G_(p) represents a protective group of the amine function preferablycleavable in an anhydrous acid medium, such as for example thecarbamates of t-butyl, trichloroethyl or trimethylsilylethyl or also thetrityl group.

Finally, the invention offers preparation processes for the compounds ofgeneral formula (I)_(H) as defined above and consisting of, for example,the reaction in a lower alcohol, such as methanol, ethanol, isopropylalcohol or t-butanol, preferably in isopropyl alcohol, at a temperaturebetween 20 and 90° C., for example at 50 ° C., and for one to 48 hours,preferably for 15 to 24 hours, optionally in the presence of DMF, of acompound of general formula (III)_(H)

with a compound of general formula (IV)_(H)

said compound of general formula (IV)_(H) optionally being able to besalified by a mineral acid G, B having the meaning indicated above and Lrepresenting a parting group and in particular an alkoxy, thioalkyl ,sulphonic acid, halide, aryl alcohol or tosyl radical (other partinggroups well-known to a person skilled in the art and being optionallyable to be used for the invention are decribed in the following work:Advanced Organic Chemistry, J. March, 3rd Edition (1985), Mc Graw-Hill,p. 315). Preferably, G represents HCl, HBr or HI.

A subject of the invention is also, as medicaments, the compounds ofgeneral formula (I), (I)_(L) or (I)_(H) described previously or theirpharmaceutically acceptable salts. It also relates to pharmaceuticalcompositions containing these compounds or their pharmaceuticallyacceptable salts, and the use of these compounds or of theirpharmaceutically acceptable salts for producing medicaments intended toinhibit neuronal NO synthase or inductible NO synthase, to inhibitlipidic peroxidation or to provide the double function of NO synthaseinhibition and lipidic peroxidation.

More preferably,(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideor a pharmaceutically acceptable salt thereof, will be used in thepharmaceutical compositions of the invention. The same will also bepreferred for producing medicaments according to the invention.

In a preferred manner, the compounds of general formula (I), (I)_(L) or(I)_(H), or their pharmaceutically acceptable salts, and in particular(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideor a pharmaceutically acceptable salt thereof, will be used produce amedicament intended to treat stroke, neurodegenerative diseases orischemic or hemorragic cardiac or cerebral infarctions, notably thoserelated with complications of coronary artery bypass grafting.

The invention therefore provides a method of treating stroke orneurodegenerative diseases comprising administering to said warm-bloodedanimal a compound of general formula (I), (I)L or (¹)H, or apharmaceutically acceptable salt thereof, and in particular(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideor a pharmaceutically acceptable salt thereof, in an amount sufficientto inhibit stroke or neurodegenerative diseases.

The invention also provides a method of preventing or treating ischemicor hemorragic cardiac or cerebral infarctions related with complicationsof coronary artery bypass grafting in a warm-blooded animal comprisingadministering to said warm-blooded animal a compound of general formula(I), (I)_(L) or (I)_(H), or a pharmaceutically acceptable salt thereof,and in particular(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideor a pharmaceutically acceptable salt thereof, in an amount sufficientto inhibit said ischemic or hemorragic cardiac or cerebral infarctions.

By pharmaceutically acceptable salt is meant in particular additionsalts of inorganic acids such as hydrochloride, sulphate, phosphate,diphosphate, hydrobromide and nitrate, or of organic acids, such asacetate, maleate, fumarate, tartrate, succinate, citrate, lactate,methane sulphonate, p-toluenesulphonate, pamoate, oxalate and stearate.The salts formed from bases such as sodium or potassium hydroxide alsofall within the scope of the present invention, when they can be used.For other examples of pharmaceutically acceptable salts, reference canbe made to “Pharmaceutical salts”, J. Pharm. Sci. 66:1 (1977).

The pharmaceutical composition can be in the form of a solid, forexample powders, granules, tablets, capsules, liposomes orsuppositories. Appropriate solid supports can be for example calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in the form of a liquid, for example, solutions,emulsions, suspensions or syrups. Appropriate liquid supports can be,for example, water, organic solvents such as glycerol or the glycols, aswell as their mixtures, in varying proportions, in water.

A medicament according to the invention can be administered by topical,oral or parenteral route, by intramuscular injection, etc.

The envisaged administration dose for the medicament according to theinvention is comprised between 0.1 mg and 10 g according to the type ofactive compound used.

According to the invention, the compounds of general formula (I)_(L) canbe prepared by the process described below.

PREPARATION OF COMPOUNDS OF GENERAL FORMULA (I)

The preparation of the compounds of general formula (I), correspondingto subformulae (I)_(L) and (I)_(H), is described hereafter.

A) Preparation of Compounds of General Formula (I)_(L)

The compounds of general formula (I)_(L) can be prepared fromintermediates of general formula (II)_(L) according to diagram 1.

The reduction of the nitro function of the intermediates of generalformula (II)_(L) is generally carried out by catalytic hydrogenation inethanol, in the presence of Pd/C, except when X=—CH═CH—CO— or Y=—O—CH₂—,the nitro group is selectively reduced using, for example, SnCl₂ (J.Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25,(8), 839-842). The reaction is then carried out by heating the mixtureto approx. 70° C., for at least three hours, in ethyl acetate, sometimeswith added ethanol.

The aniline derivatives of general formula (III)_(L) thus obtained canbe condensed on derivatives of general formula (IV)_(L), for examplederivatives of O-alkyl thioimidate or S-alkyl thioimidate type, in orderto produce final compounds of general formula (I)_(L) (cf. diagram 1).For example, for B=thiophene, the derivatives of general formula(III)_(L) can be condensed on S-methylthiophene thiocarboxamidehydriodide, prepared according to a method in the literature (Ann. Chim.(1962), 7, 303-337). Condensation can be carried out by heating in analcohol (for example in methanol or isopropanol), optionally in thepresence of DMF at a temperature comprised between 50 and 100° C. for aduration generally comprised between a few hours and overnight.

Preparation of Intermediates of General Formula (II)_(L)

The intermediates of general formula (II)_(L) can be prepared bydifferent processes depending on the chemical functions which are setup: amines, carboxamides, ureas, thioureas, sulphonamides,aminosulphonylureas, sulphamides, carbamates, ethers, esters,thioethers, acylureas, etc.:

When:

X=linear or branched alkylene radical having from 1 to 6 carbon atomsand

Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—

The amines of general formula (II)_(L), diagram 2, in which A, X, Y andR₆ are as defined above, can be obtained by nucleophile substitution ofthe halogenated derivatives of general formula (VI)_(L) by an amine ofgeneral formula (VII)_(L). The reaction is carried out, for example, inDMF in the presence of K₂CO₃ at 20° C. The halogenated derivatives ofgeneral formula (VI)_(L) can be accessed, for example, by bromation ofthe primary alcohols of general formula (V)_(L) using PBr₃, at 0° C., inanhydrous THF. The alcohols of general formula (V)_(L) which are notcommercially available can be prepared according to methods described inthe literature (Tetrahedron Lett. (1983), 24, (24), 2495-2496).

The amines of general formula (VII)_(L) in which Y representshomopiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine or moregenerally —NR₃—Z₂—NR₃— are synthesized in three stages from thecorresponding commercial diamines. The diamines are selectivelymono-protected in the form of the carbamate (Synthesis (1984), (12),1032-1033; Synth. Commun. (1990), 20, (16), 2559-2564) before reactionby nucleophile substitution on a fluoronitrobenzene, in particular4-fluoronitrobenzene. The amines, previously protected, are released atthe last stage, according to methods described in the literature (T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, SecondEdition (Wiley-Interscience, 1991)), in order to produce intermediatesof general formula (VII)_(L).

When:

X=—Z₁—CO—, —CH═CH—CO— and

Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—

The carboxamides of general formula (II)_(L), diagram 3, in which A, X,Y and R₆ are as defined above, are prepared by condensation of thecommercial carboxylic acids of general formula (VIII)_(L) for X=—Z₁—CO—and of general formula (IX)_(L) for X=—CH═CH—CO— with amines of generalformula (VII)_(L). The non commercial acids can be synthesized accordingto methods similar to those described in the literature (J. Org. Chem.(1974), 39 (2), 219-222; J. Amer. Chem. Soc. (1957), 79, 5019-5023, andCHIMIA (1991), 45 (4), 121-123 when A represents a6-alkoxy-2,5,7,8-tetramethylchromane radical). The amines of generalformula (VII)_(L) in which Y represents homopiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, or more generally—NR₃—Z₂—NR₃— are prepared according to methods similar to thosedescribed in the previous paragraph. The carboxamide bonds are formedunder standard conditions for peptide synthesis (M. Bodanszky and A.Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag,1984)) in THF, dichloromethane or DMF in the presence of a couplingreagent such as dicyclohexylcarbodiimide (DCC), 1,1′-carbonyldiimidazole(CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC orWSCI) (John Jones, The chemical synthesis of peptides, 54 (ClarendonPress, Oxford, 1991)).

When:

X=—Z₁—NR₃—CO— and

Y=—Z₂—Q—

The carboxamides of general formula (II)_(L) in which A, X, Y and R₆ areas defined above can also be prepared, as in diagram 4, by peptidecondensation of an amine of general formula (X) with a commercial acidof general formula (XI)_(L). When X=—NR₃—CO— and R₃=H, the compounds ofgeneral formula (X)_(L) are anilines which are obtained byhydrogenation, in the presence of a catalytic quantity of Pd/C, thecorresponding nitrobenzene derivatives, themselves synthesized accordingto a method described in the literature (J. Org. Chem. (1968), 33 (1),223-226). When X #—NR₃—CO— and R₃ is a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms, the monoalkylamines can be obtainedaccording to a process described in the literature (U.S. Pat. Nos.3,208,859 and 2,962,531). The non-commercial carboxylic acids of generalformula (XI)_(L) can be accessed using methods described in theliterature (Acta Chem. Scand. (1983), 37, 911-916; Synth. Commun.(1986), 16 (4), 479-483; Phophorus, Sulphur Silicon Relat. Elem. (1991),62, 269-273).

When:

X=—Z₁—NR₃—CO— and

Y=—NH—Z₂—Q—, —NH—CO—Z₂—Q— with Q=O—Z₃—, R₃—N—Z₃— or S—Z₃—,

The ureas of general formula (II)_(L), diagram 5, in which A, X, Y andR₆ are as defined above, are prepared by the addition of an amine ofgeneral formula (X)_(L) on an isocyanate of general formula (XII)_(L),(XIII)_(L) or (XIV)_(L) in a solvent such as chloroform at 20° C.Synthesis of non-commercial isocyanates of general formula (XII)_(L) isdescribed in the literature (J. Med. Chem. (1992), 35 (21), 3745-3754).The halogenated intermediate ureas (XV)_(L) and (XVII)_(L) are thensubstituted by a derivative of general formula (XVI)_(L), in which Qrepresents O—Z₃—, R₃—N—Z₃— or S—Z₃—, in the presence of a base such as,for example, K₂CO₃ or NaH in an aprotic solvent such as THF or DMF inorder to finally obtain ureas of general formula (II)_(L).

When:

X=—Z₁—NH—CO— and

Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—

The ureas of general formula (II)_(L), diagram 6, in which A, X, Y andR₆ are as defined above, are prepared by the addition of an amine ofgeneral formula (VII)_(L), described previously, onto an isocyanate ofgeneral formula (XVIII)_(L) in the presence of a base such asdiisopropylethylamine.

The isocyanates of general formula (XVIII)_(L) are synthesized fromprimary amines of general formula (X)_(L), described previously,triphosgene and a tertiary amine (J. Org. Chem. (1994), 59 (7),1937-1938).

The amines of general formula (VII)_(L) in which Y #—NH—O— are preparedaccording to a method described in the literature (J. Org. Chem. (1984),49 (8), 1348-1352).

When:

X—Z₁—NR₃—CO— and

Y=—NR₃—SO₂—NR₃—Z₂—

The aminosulphonylureas of general formula (II)_(L), diagram 7, in whichA, X, Y and R₆ are as defined above, are prepared by the addition ofamines of general formula (X)_(L), described previously, ontochlorosulphonylisocyanate (J. Med. Chem. (1996), 39 (6), 1243-1252). Theintermediate chlorosulphonylurea (XIX)_(L) is then condensed on theamines of general formula (VII)_(L), described previously, in order toproduce the aminosulphonylureas of general formula (II)_(L) which canoptionally be alkylated by a halogenated derivative in the presence of abase such as, for example, NaH in order to produce other derivatives ofgeneral formula (II)_(L).

When:

X=—Z₁—NR₃—SO₂— and

Y=—Z₂—Q—, with Q=O—Z₃—, R₃—N—Z₃— or S—Z₃—,

The sulphonamides of general formula (II)_(L) diagram 8, in which A, X,Y and R₆ are as defined above, are prepared by the addition of amines ofgeneral formula (X)_(L), described previously, ontohalogenoalkylsulphonyl chlorides of general formula (XX)_(L). Thehalogenoalkylsulphonamides of general formula (XXI)_(L), obtainedintermediately, are then condensed on an alcohol, an amine or a thiol ofgeneral formula (XVI)_(L) in the presence of a base such as, forexample, K₂CO₃ or NaH, in a polar solvent such as, for example,acetonitrile or DMF.

When:

X=—Z₁—NR₃—SO₂— and

Y=—NR₃—Z₂—Q—

The sulphamides of general formula (II)_(L), diagram 9, in which A, X, Yand R₆ are as defined above are prepared in three stages from amines ofgeneral formula (X)_(L) and chlorosulphonylisocyanate. The reaction ofan alcohol, such as tBuOH, on the isocyanate function ofchlorosulphonylisocyanate (Tetrahedron Lett. (1991), 32 (45), 6545-6546)leads to an intermediate of chlorosulphonylcarbamate type, which reactsin the presence of an amine of general formula (X)_(L) to produce aderivative of carboxylsulphamide type of general formula (XXII)_(L). Thetreatment of this intermediate in a strong acid medium produces thesulphamide derivative of general formula (XXIII)_(L). Alkylation of thecompounds of general formula (XXIII)_(L) by the halogenated derivativesof general formula (XXIV)_(L) in the presence of a base such as, forexample, NaH in a polar aprotic solvent allows sulphamide derivatives ofgeneral formula (II)_(L) to be obtained.

When:

X=—Z₁—NR₃—CO— and

Y=—O—Z₂—Q—

The carbamates of general formula (II)_(L), diagram 10, in which A, X, Yand R₆ are as defined above, are prepared by the reaction of amines ofgeneral formula (X)_(L), described previously, with chloroformatederivatives of general formula (XXV)_(L) prepared according to a methoddescribed in the literature (Tetrahedron Lett. (1993), 34 (44),7129-7132).

When:

X=—Z₁—CO—, —CH═CH—CO— and

Y=—O—Z₂—Q—

The esters of general formula (II)_(L), diagram 11, in which A, X, Y andR₆ are as defined above, are prepared by the reaction of acids ofgeneral formula (VIII)_(L) or (IX)_(L) and alcohols of general formula(XXVI)_(L) in the presence de dicyclohexylcarbodiimide and of acatalytic quantity of 4-dimethylaminopyridine in a solvent such as, forexample, THF or DMF at 20° C.

When:

X=—Z₁— and

Y=—O—CO—Z₂—Q—

The esters of general formula (II)_(L), diagram 12, in which A, X, Y andR₆ are as defined above, can also be prepared by the reaction of acidsof general formula (XI)_(L), described previously, with the alcohols ofgeneral formula (V)_(L) under the conditions described previously.

When:

X=—Z₁—NR₃—CS— and

Y=—NH—Z₂—Q—, piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃—Z₂—Q—, —NH—NH—Z₂—,—NR₃—O—Z₂—

The thioureas of general formula (II)_(L) in which A, X, Y and R₆ are asdefined above, are prepared from the ureas described previously usingLawesson's reagent, following an experimental protocol described in theliterature (J. Med. Chem. (1995), 38 (18), 3558-3565).

When:

X represents a bond

Y=—O—Z₂—Q—, —S—Z₂—Q— and

Q=—HN—

The etheroxides or thioetheroxides of general formula (II)_(L), diagram13, in which A, X, Y and R₆ are as defined above are prepared fromdihydroquinones of general formula (XXVII)_(L) (J. Chem. Soc., PerkinTrans. I, (1981), 303-306) or thiophenols of general formula(XXVIII)_(L) (Bio. Med. Chem. Letters, (1993), 3 (12), 2827-2830) and anelectrophile (E⁺) such as, for example, bromoacetonitrile or4-nitrophenyloxazolinone, in the presence of K₂CO₃ (J. HeterocyclicChem., (1994), 31, 1439-1443). The nitriles must be reduced (lithiumhydride or catalytic hydrogenation) in order to produce intermediates ofgeneral formula (XXIX)_(L) or (XXX)_(L). The opening of thenitrophenyloxazolinones, accessible by reaction of the correspondingnitroanilines with chloroethylchloroformate as described in theliterature (J. Am. Chem. Soc., (1953), 75, 4596), by phenols orthiophenols leads directly to compounds of general formula (XXIX)_(L) or(XXX)_(L) which are then condensed on fluoronitrobenzene in order toproduce intermediates of general formula (II)_(L).

When:

X represents —Z₁—CO— or —CH═CH—CO—

Y=—NR₃—CO—Q— and

Q=R₃—N—Z₃

The acylureas of general formula (II)_(L), diagram 14, in which A, X, Yand R₆ are as defined above are prepared by condensation of acids ofgeneral formula (VIII)_(L) or (IX)_(L), diagram 3, and ureas of generalformula (XXXI)_(L) in the presence of a coupling agent usually used inpeptide synthesis, as described previously, in a solvent such as, forexample, dichloromethane or DMF. The ureas of general formula (XXXI)_(L)are accessible from isocyanates of general formula (XII)_(L), diagram 5,according to a method in the literature (J. Chem. Soc., Perkin Trans. 1,(1985), (1), 75-79).

B) Preparation of Compounds of General Formula (I)_(H)

The compounds of general formula (I)_(H) can be prepared starting fromintermediates of general formula (II)_(H), (III)_(H) or (V)_(H)according to diagram 15.

The reduction of the nitro function of the intermediates of generalformula (II)_(H) is generally carried out by catalytic hydrogenation inethanol, in the presence of Pd/C, except when the molecules contain anunsaturation or a sulphur atom, this being a poison to the Pd/C. In thiscase, the nitro group is selectively reduced, for example, by heatingthe product in solution in ethyl acetate with a little ethanol in thepresence of SnCl₂ (J. Heterocyclic Chem. (1987), 24, 927-930;Tetrahedron Letters (1984), 25, (8), 839-842) or by using Raney Ni withhydrazine hydrate added to it (Monatshefte für Chemie, (1995), 126,725-732).

The aniline derivatives of general formula (III)_(H) thus obtained canbe condensed on derivatives of general formula (IV)_(H), for examplederivatives of O-alkyl thioimidate or S-alkyl thioimidate type, in orderto produce final compounds of general formula (I)_(H) (cf. diagram 15).For example, for B=thiophene, the derivatives of general formula(III)_(H) can be condensed on S-methylethiophene thiocarboxamidehydriodide, prepared according to a method in the literature (Ann. Chim.(1962), 7, 303-337). Condensation can be carried out by heating in analcohol (for example in methanol or isopropanol), optionally in thepresence of DMF at a temperature comprised between 50 and 100° C. for aduration generally comprised between a few hours and overnight.

The final molecules of general formula (I)_(H) are also accessiblethrough another synthetic route passing through the intermediates ofgeneral formula (V)_(H) which carry a heterocyclic amine functionprotected by a protective group “G_(p)”, for example a2-(trimethylsilyl)ethoxymethyl group (SEM) or by another protectivegroup mentioned in: Protective groups in organic synthesis, 2d ed.,(John Wiley & Sons Inc., 1991). The reduction and condensation stageswhich lead to intermediates (VI)_(H) and (VII)_(H) respectively arecarried out under the same conditions as those described previously. Thelast stage of the synthesis consists in regenerating, for example in anacid medium or in the presence of a fluoride ion, the protectedheterocyclic amine function.

Alternatively, the intermediates of general formula (V)_(H) can beconverted directly into the intermediate of general formula (II)_(H) byrelease of the heterocyclic amine by treatment, for example, in an acidmedium or in the presence of a fluoride ion.

Preparation of the Compounds of General Formula (II)_(H), (III)_(H) and(V)_(H)

The intermediates of general formula (II)_(H), (III)_(H) and (V)_(H) canbe prepared by the different synthetic routes illustrated below.

When:

Het=Imidazole, tetrahydropyridine, thiazolidine, dihydroimidazole-2-oneand

Y=—Y′—.

The amines of general formula (II)_(H), diagram 16, in which A, X, Y andHet are as defined above, can be obtained by nucleophilic substitutionof commercial halogenated derivatives of general formula (IX)_(H) by aheterocyclic amine of general formula (VIII)_(H). The reaction iscarried out in acetonitrile, THF or DMF in the presence of a base suchas K₂CO₃ at a temperature varying from 20 to 110° C. The synthesis ofheterocyclic derivatives of general formula (VIII)_(H), which are notcommercially-available, is described below.

When:

Het=imidazole, thiazolidine, tetrahydropyridine and

Y=—Y′—.

The heterocyclic amines of general formula (III)_(H), diagram 17, inwhich A, X, Y and Het are as defined above, are prepared in two stagesstarting from the amines of general formula (VIII)_(H) (see below). Themixture of a brominated derivative of general formula (X)_(H), thesynthesis of which is explained in detail below, with an amine ofgeneral formula (VIII)_(H) in a solvent such as acetonitrile or DMF inthe presence of a base leads to intermediates of general formula(XI)_(H). The deprotection of the amine function, in an organic acidmedium, allows the compounds of general formula (III)_(H) to beobtained.

When:

Het=thiazolidine and

Y=—CO—Y′—.

The carboxamides of general formula (III)_(H), diagram 18, in which A,X, Y and Het are as defined above, are prepared by condensation of theamines of general formula (VIII)_(H), decribed previously, with thecarboxylic acids of general formula (X.2)H. The carboxamide bonds areformed under standard conditions of peptide synthesis (M. Bodanszky andA. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag,1984)) in THF, dichloromethane or DMF in the presence of a couplingreagent such as dicyclohexylcarbodiimide (DCC), 1,1′-carbonyldiimidazole(CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC orWSCI) (John Jones, The chemical synthesis of peptides, 54 (ClarendonPress, Oxford, 1991)). The synthesis of the carboxylic acids of generalformula (X.2)_(H) is described below. The intermediates of generalformula (XII)_(H) are then deprotected in an acid medium using, forexample, trifluroroacetic acid or an organic solution of HCl.

When:

Het=thiazolidine and

Y=—CO—NH—Y′—.

The carboxamides of general formula (V)_(H), diagram 19, in which A, X,Y and Het are as defined above, are prepared by condensation ofcarboxylic acids of general formula (XIII)_(H) with the commercialamines of general formula (XIV)_(H) under standard conditions forpeptide synthesis. The synthesis of the carboxylic acids of generalformula (XIII)_(H) is described below.

When:

Het=thiazole, furan, pyrrole, tetrahydropyridine, pyrrolidine and

X=—NH—CO—X′—.

The carboxamides of general formula (II)_(H), diagram 20, in which A, X,Y and Het are as defined above, are prepared by condensation of anilinesof general formula (XV)_(H) with the carboxylic acids of general formula(XVI)_(H) under standard conditions for peptide condensation. Theanilines of general formula (XV)_(H) are obtained by hydrogenation, inthe presence of a catalytic quantity of Pd/C, of correspondingnitrobenzene derivatives, themselves synthesized according to a methoddescribed in the literature (J. Org. Chem. (1968), 33 (1), 223-226). Theacids of general formula (XVI)_(H), diagram 20, which are notcommercially available, are prepared according to methods described inthe literature.

The synthesis of pyrroles is described in Chem. Heterocycl. Compd.,1982, 18, 375. The substitued prolines are accessible starting fromcommercial hydroxyprolines and are prepared according to methodsdescribed in J. Org. Chem., 1991, 56, 3009.

The synthesis of the thiazole and tetrahydropyridine derivatives isdescribed below.

When:

Het=hydantoin and

Y=—Y′—.

The hydantoins of general formula (II)_(H), diagram 21, in which A, X, Yand Het are as defined above, are prepared in 3 stages starting from theanilines of general formula (XV)_(H) described previously. Thesubstitution of the aniline by ethyl bromoacetate is carried out in thepresence of sodium acetate in ethanol at a temperature of approximately60-70° C. The monosubstitution product of general formula (XVII)_(H) isthen condensed on an isocyanate of general formula (XVIII)_(H) in anorganic solvent such as, for example, dichloromethane, at a temperatureof approximately 20° C. The cyclization of urea (XIX)_(H) is carried outby heating, at 50° C., in ethanol, according to an experimental protocoldescribed in the literature (J. Heterocyclic Chem., (1979), 16,607-608). The isocyanates of general formula (XVIII)_(H) are synthesisedstarting from the corresponding commercial primary amines, triphosgeneand a tertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938).

When:

Het=thiazolidinone and

Y=—Y′—.

The thiazolidinones of general formula (II)_(H), diagram 22, in which A,X, Y and Het are as defined above, are prepared starting from commercialamines of general formula (XIV)_(H) and aldehydes of general formula(XX)_(H) in the presence of mercaptoacetic acid according to anexperimental protocol described in the literature (J. Med. Chem.,(1992), 35, 2910-2912).

When:

Het=hydantoin

X=—CH═and Y=—Y′—.

The hydantoines of general formula (II)_(H), diagram 23, in which A, X,Y and Het are as defined above, are prepared in 2 stages starting fromthe isocyanates of general formula (XVIII)_(H) described previously. Thereaction of the ethyl ester of sarcosine with the isocyanates of generalformula (XVIII)_(H), is carried out according to an experimentalprotocol described in the literature (J. Heterocyclic Chem., (1979), 16,607-608), leads to the formation of the heterocycle of the compounds ofgeneral formula (XXI)_(H). The substitution of the hydantoin is carriedout in the presence of a weak base, β-alanine, and an aldehyde ofgeneral formula (XX)_(H) according to the experimental conditionsdescribed in J. Med. Chem., (1994), 37, 322-328.

When:

Het=pyrrolidine, thiazolidine

X=—NH—CO—X′— and Y=—O—Y′— or —Y′—.

The carboxamides of general formula (V)_(H), diagram 24, in which A, X,Y and Het are as defined above, are prepared by condensation of theanilines of general formula (XV)_(H), described previously, with theacids of general formula (XXII)_(H) under standard conditions forpeptide synthesis. The syntheses of carboxylic acids (XXII)_(H), whichare nont commercially available, are described below.

When:

Het=tetrahydropyridine and

Y=—CO—NH—Y′—.

The ureas of general formula (II)_(H), diagram 25, in which A, X, Y andHet are as defined above, are prepared by condensation of theheterocyclic amines of general formula (VIII)_(H), described previously,with the isocyanates of general formula (XVIII)_(H) (cf. above) in asolvent such as dichloromethane, at 20° C., in the presence of atertiary amine (e.g. Diisopropylethylamine).

When:

Het=pyrrolidine, thiazole, thiadiazole and

X=—CO—NH—X′—.

The carboxamides of general formula (II)_(H), diagram 26, in which A, X,Y and Het are as defined above, are prepared by condensation ofcommercial carboxylic acids of general formula (XXIII)_(H) with theamines of general formula (XXIV)_(H) under standard conditions forpeptide synthesis. The syntheses of the amines of general formula(XXIV)_(H), which are not commercially available, are described below.

When:

Het=imidazole, oxazole and thiazole and

Y=—CH(R₃)—N(R₃)—CO—Y′—.

The carboxamides of general formula (V)_(H), diagram 27, in which A, X,Y and Het are as defined above, are prepared by condensation of theamines of general formula (XXV)_(H) with commercial carboxylic acids (orthe corresponding acid chlorides) of general formula (XXVI)_(H) understandard conditions for peptide synthesis. The synthesis of theimidazole derivatives of general formula (XXV)_(H) is described below.

When:

Het=imidazole and

Y=—CH₂—N(R₃)—Y′—.

The amines of general formula (V)_(H), diagram 28, in which A, X, Y andHet are as defined above, are prepared by condensation of the amines ofgeneral formula (XXV)_(H) (see below) with the commercial halogenatedderivatives of general formula (IX)_(H) under the conditions describedpreviously.

When:

Het=dihydroimidazole-2-one and

Y=—CO—Y′.

The amines of general formula (II)_(H), diagram 29, in which A, X, Y andHet are as defined above, are prepared by condensation of the amines ofgeneral formula (VIII)_(H) (see below) with the commercial halogenatedderivatives of general formula (XXVII)_(H), for example in anacetonitrile and THF mixture and in the presence of a base such asK₂CO₃.

When:

Het=oxazolidinone and

Y=—Y′—O—.

The oxazolidinones of general formula (II)_(H), diagram 30, are preparedstarting from the diols of general formula (XXVII)_(H) the synthesis ofwhich is described in the literature (Daumas, M., Tetrahedron, 1992,48(12), 2373). The formation of carbonates of general formula(XXVIII)_(H) is obtained, for example, in the presence of carbonyldi-imidazole (Kutney, J. P., Synth. Commun., 1975, 5(1), 47) or in thepresence of triphosgene at low temperature as described in Synth.Commun., 1994, 24(3), 305. The formation of oxazolidinone occurs duringheating of the amines of general formula (XV)_(H) with the carbonates ofgeneral formula (XXVIII)_(H) in the presence of an acid catalyst, suchas ZnCl₂, to xylene reflux in order to eliminate the water formed duringthe reaction (Laas, H., Synthesis, 1981, 958).

When:

Het=isoxazoline, isoxazole, oxazole, thiazole and

Y=—Y′—CO—NH—Y′—

The carboxamides of general formula (II)_(H), diagram 3 1, in which A,X, Y and Het are as defined above, can be prepared starting from thecommercial amines of general formula (XIV)_(H) and the carboxylic acidsof general formula (XXVIII)_(H) by condensation in the presence ofisobutyl chloroformate (Org. Prep. Proced. Int., (1975), 7, 215).

The preparation of the oxazoles of general formula (XXVIII)_(H) iscarried out according to an experimental protocol described inTetrahedron Lett., 1994, 35 (13), 2039. Similarly for the synthesis ofthe thiazoles of general formula (XXVIII)_(H) : J. Med. Chem., 1983, 26,884. The preparation of the isoxazolines is described below.

When:

Het=pyrrolidine, piperidine

X=—CO—NH— and

Y=—O—Y′—.

The carboxamides of general formula (II)_(H), diagram 32, in which A, X,Y and Het are as defined above, can be prepared by condensation of thecommercial carboxylic acids of general formula (XXIII)_(H) with theamines of general formula (XXIX)_(H) under standard conditions forpeptide synthesis. The syntheses of amines of general formula (XXIX)_(H)are described below.

When:

Het=isoxazoline, oxazole, thiazole, imidazole and

Y=—Y′—O—Y′— or —Y′—N(R₃)—Y′—.

The etheroxides of general formula (II)_(H), Diagram 33, in which A, X,Y and Het are as defined above, can be prepared starting from the estersof general formula (XXVIII.4)_(H), diagram 31.1, by reaction withhydrides, for example LiA1H₄, in a solvent such as, for example,anhydrous THF. The primary alcohols thus obtained are then condensed onhalogenated derivatives of general formula (IX)_(H) using a base such asfor example KOH in an organic medium and in the presence of a phasetranfer catalyst such as for example Aliquat 336.

The primary alcohols (XXXI)_(H) can also be activated in the form ofsulphonate derivatives, by tosyl chloride in the presence of pyridine,in order to produce intermediates of general formula (XXXII)_(H). Thecondensation of alcohols of general formula (XXII.2)_(H) is then carriedout in the presence of a strong base, such as, for example, NaH, in anaporotic solvent (THF or DMF) at a temperature comprised between 20° C.and 80° C., in order to obtain the ether oxide of general formula(H)_(H).

Similarly, the amines of general formula (II)_(H), diagram 33, areobtained by the substitution of the tosylate function of theintermediates of general formula (XXXII)_(H), obtained in a standardfashion starting from the alcohols of general formula (XXXI)_(H) andtosyl chlosride in the presence of pyridine, by the commercial amines ofgeneral formula (XXX)_(H) by reaction in a solvent such as, for example,acetonitrile or DMF, in the presence of a base (K₂CO₃) at a temperaturecomprised between 20 and 85° C.

When:

Het=azetidine

X=—CO—NH— and

Y=—O—Y′—.

The carboxamides of general formula (III)_(H), diagram 34, in which A,X, Y and Het are as defined above, can be prepared by condensation ofcommercial carboxylic acids of general formula (XXIII)_(H) with theamines of general formula (XXXII)_(H) under standard conditions forpeptide synthesis. The synthesis of amines of general formula(XXXII)_(H) is descried below. The deprotection of the aniline iscarried out by a strong acid such as, for example, trifluoroacetic acidoptionally in the presence of triethylsilane.

When:

Het=azetidine

X=—NH—CO—X′— and

Y=—O—Y′—.

The ureas of general formula (III)_(H), diagram 35, in which A, X, Y andHet are as defined above, can be prepared by the addition of the aminesof general formula (XXXII)_(H) on the isocyanates (XXXIV)_(H) obtainedfrom the reaction of the amines of general formula (XV)_(H) withtriphosgene in the presence of a tertiary amine such as for examplediisopropylethylamine in a neutral solvent such as dichloromethane (J.Org. Chem. (1994), 59 (7), 1937-1938). The ureas of general formula(XXXV)_(H) thus obtained are deprotected by treatment in a strong acidmedium as described previously. The synthesis of the amines of generalformula (XXXII)_(H) is described below.

When:

Het=thiazole and

Y=—CH₂—N(R₃)—Y′—.

The amines of general formula (II)_(H), diagram 36, in which A, X, Y andHet are as defined above, are prepared by condensation of the amines ofgeneral formula (XXV)_(H) (see below) with the commercial halogenatedderivatives of general formula (IX)_(H) under the conditions describedpreviously.

Preparation of Different Synthesis Intermediates

Synthesis of Intermediates (VIII)_(H)

The syntheses of the intermediates of general formula (VIII)_(H) areillustrated in diagrams 16.1 and 16.2.

The intermediates of general formula (VIII)_(H), diagram 16.1, can beprepared, for example, in 3 stages starting from 4-imidazole carboxylicacid. The protection of the nitrogen of the heterocycle is carried outusing (Boc)₂O in the presence of a base such as K₂CO₃ in DMF. Thecondensation with the amines of general formula (XV)_(H) (see above) iscarried out in a standard fashion under the conditions for peptidesynthesis in order to produce the intermediates of general formula(VIII.3)_(H). The amine of the heterocycle is regenerated by treatmentin an acid medium and in particular with trifluoroacetic acid in orderto produce the intermediates of general formula (VIII)_(H).

The dihydroimidazole-2-ones of general formula (VIII)_(H), diagram 16.2,can be prepared, for example, in 2 stages starting from the anilines ofgeneral formula (XV)_(H) (see above) which are condensed on2-chloroethyl isocyanate in DMF at 20° C. in order to produce the ureasof general formula (VIII.4)_(H). The cyclization to produce (VIII)_(H)is then carried out by treatment in a basic medium using, for example,tBuOK in DMF.

Synthesis of Intermediates (X)_(H)

The intermediates of general formula (X)_(H), diagram 17.1, can beprepared starting from commercial carboxylic acids of general formula(X.1)_(H). Protection of the amine function in the form of a carbamateis followed by the selective reduction of the carboxylic acid functionby lithium and aluminium hydride in a solvent such as THF, at 20° C.Intermediaite (X.3)_(H) is then brominated in the presence of carbontetrabromide and triphenylphosphine in a solvent such asdichloromethane.

Synthesis of Intermediates (XIII)_(H)

The intermediates of general formula (XIII)_(H), diagram 19.1, can beprepared starting from (R or S) derivatives of thiazolidine carboxylicacids in the presence of (Boc)₂O under standard conditions.

Synthesis of Intermediates (XVI)_(H)

The intermediates of general formula (XVI)_(H), diagram 20.1, can beprepared starting from commercial carboxamide derivatives of generalformula (XVI.1)_(H). These carboxamides are treated by a Lawessonreagent in a solvent such as 1,4-dioxane for 2 to 3 hours at atemperature which varies from 25° C. to reflux temperature of themixture. The thiocarboxamides of general formula (XVI.2)_(H) are thentreated by ethyl bromopyruvate, at 20° C. in DMF according to anexperimental protocol described in J. Med. Chem., (1983), 26, 884-891,in order to produce the thiazoles of general formula (XVI.3)_(H). Thesaponification of the ester is carried out over 15 hours by aqueouspotash in solution in acetone.

The tetrahydropyridines of general formula (XVI)_(H), diagram 20.2, canbe prepared starting from commercial tetrahydro-4-pyridinecarboxylicacid. Esterification is carried out in a standard fashion inthe presence of para-toluene sulphonic acid, in methanol, in order toproduce to the intermediaire (XVI.4)_(H) which is then condensed on ahalogenated derivative of general formula (IX)_(H) under the conditionsdescribed previously. The acid of general formula (XVI)_(H) is obtainedby saponification in the presence of, for example, LiOH or KOH.

Synthesis of Intermediates (XXII)_(H)

The syntheses of intermediates of general formula (XXII)_(H) aredescribed in diagrams 10.1 and 10.2.

The tosyylate function of the (L or D) proline derivatives of generalformula (XXII.1)_(H) (Tetrahedron Lett., (1983), 24 (33), 3517-3520),diagram 24.1, is substituted by the alcoholate of the derivaties ofgeneral formula (XXII.2)_(H), generated in situ by a base such as NaH.The substitution is carried out at 20° C. in a solvent such asN-methylpyrrolidinone which produces the appropriate inversion of theconfiguration of the carbon seat of the reaction (Tetrahedron Lett.,(1983), 24 (33), 3517-3520). The intermediates of general formula(XXII.3)_(H) thus obtained are then saponified in a standard fashion byalcoholic potash.

The intermediates of general formula (XXII)_(H) can also be prepared(diagram 24.2) starting from the condensation of cysteine (L or D) on analdehyde of general formula (XXII.5)_(H) according to an experimentalprotocol described in the literature (J. Org. Chem., (1957), 22,943-946). The amine of the heterocycle is then protected in the form ofa carbamate in order to produce intermediates of general formula(XXII)_(H). The aldehydes of general formula (XXII.5)_(H), which are notcommercially available, can be prepared according to J. Chem. Soc.,Perkin Trans. I, 1973, 1, 35.

Synthesis of Intermediates (XXIV)_(H)

The synthesis of intermediates of general formula (XXIV)_(H) isdescribed in diagram 26.1.

The condensation of the amines (R or S) of general formula (XXIV.1)_(H),diagram 26.1, on the halogenated derivatives of general formula (IX)_(H)is carried out in the presence of a base such as potassium carbonate ina solvent such as DMF. The condensation product (XXIV.2)_(H) is thendeprotected in an acid medium in order to produce intermediates ofgeneral formula (XXIV)_(H).

Synthesis of Intermediates (XXV)_(H)

The syntheses of intermediates of general formula (XXV)_(H) aredescribed in diagrams 27.1, 27.2, 27.3 and 27.4.

The imidazoles of general formula (XXV)_(H), diagram 27.1, can beprepared in 4 stages starting from the commercial compounds (XXV.1)_(H)and (XXV.2)_(H).

The condensation between the bromoacetophenones of general formula(XXV.1)_(H) and the carboxylic acids of general formula (XXV.2)_(H) iscarried out in the presence of Caesium carbonate in DMF. The ketoesterobtained (XXV.3)_(H) is cyclized in the presence of 15 equivalents ofammonium acetate by heating in a mixture of xylenes and simultaneouselimination of the water formed during the reaction in order to producethe imidazoles of general formula (XXV.4)_(H). The nitrogen of theheterocycle is then protected, for example using2-(trimethylsilyl)ethoxymethyl (SEM) or by another protective groupmentioned in: Protective groups in organic synthesis, 2nd ed., (JohnWiley & Sons Inc., 1991), in order to produce intermediates of generalformula (XXV.5)_(H). The release of the amine from the chain can becarried out by hydrogenolysis in the presence of Pd/C.

Alternatively, the intermediates of general formula (XXV.4)_(H) can bealkylated in the presence of a base such as, for example, K₂CO₃, and areagent such as R₃—X in a solvent such as DMF or acetonitrile in orderto produce the imidazoles of general formula (XXV.6)_(H). Deprotectionof the side chain, as described previously, allows the intermediates ofgeneral formula (XXV)_(H) to be accessed.

The intermediates of general formula (XXV)_(H) containing an oxazole,thiazole or an imidazole are also accessible via other synthetic routessuch as that described in Bioorg. and Med. Chem. Lett., 1993, 3, 915 orTetrahedron Lett., 1993, 34, 1901. The intermediates of general formula(XXV.7)_(H) thus obtained can be modified, diagram 27.2, bysaponification followed by decarboxylation, for example thermic, inorder to produce disubstituted heterocycles of general formula(XXV.9)_(H). Release of the amine from the side chain, as describedpreviously, allows the intermediates of general formula (XXV)_(H) to beaccessed.

Alternatively, the carboxylic function of the heterocycles of generalformula (XXV.7)_(H), can be reduced, for example by NaBH₄, in order toproduce alcoholic derivatives of general formula (XXV.10)_(H), diagram27.3, which can be alkylated in the presence of R₃—X and a base such asK₂CO₃ in a solvent such as acetonitrile or DMF. Release of the aminefrom the side chain, as described previously, allows the intermediatesof general formula (XXV)_(H) to be accessed.

The thiazoles of general formula (XXV)_(H), diagram 27.4, can also beprepared in 4 stages starting from commercial sarcosinamidehydrochloride. The amine is first protected in a standard fashion in theform of tBu carbamate and the carboxamide function is converted intothiocarboxamide in the presence of Lawesson reagent. The formation ofthe thiazole ring is carried out by the reaction of thiocarboxamide withthe intermediate of general formula (XXV.1)_(H) according to anexperimental protocol described in the literature (J. Org. Chem.,(1995), 60, 5638-5642). The amine function is regenerated by treatmentwith the intermediate of general formula (XXV.12)_(H) in a strong acidmedium such as, for example, trifluoroacetic acid.

Synthesis of Intermediates (XXVIII)_(H)

The isoxazolines and isoxazoles of general formula (XXVIII)_(H), Diagram31.1, are prepared by reaction of commercial aldehydes of generalformula (XX)_(H) with hydroxylamine hydrochloride. The oxime of generalformula (XXVIII.1)_(H) thus obtained is activated in the form of theoxime chloride, of general formula (XXVIII.2)_(H), by reaction withN-chlorosuccinimide in DMF before reacting with the esters of generalformula (XXVIII.3)_(H) in order to produce isoxazoline derivatives orwith the esters of general formula (XXVIII.4)_(H) in order to produceisoxazole derivatives according to an experimental protocol described inthe literature (Tetrahedron Lett., 1996, 37 (26), 4455; J. Med. Chem.,1997, 40, 50-60 and 2064-2084). Saponification of the isoxazolines orisoxazoles of general formula (XXVIII.5)_(H) is then carried out in astandard fashion under the conditions described previously.

The unsaturated esters of general formula (XXVIII.3)_(H) and(XXVIII.4)_(H), which are not commercially available, can be preparedaccording to methods described in the literature (J. Med. Chem., 1987,30, 193; J. Org. Chem., 1980, 45, 5017).

Synthesis of Intermediates (XXIX)_(H)

The syntheses of intermediates of general formula (XXIX)_(H) aredescribed in diagrams 32.1, 32.2, 32.3 and 32.4

The intermediates of general formula (XXIX)_(H) can be prepared, diagram32.1, starting from the intermediates of general formula (XXII.3)_(H),described previously, by treatment in a strong acid medium to regeneratethe heterocyclic amine function. The selective reduction of thecarboxylic function in the presence of, for example, sodium borohydridein a solvent such as, for example, anhydrous THF, allows theintermediate of general formula (XXIX)_(H) carrying a primary alcoholfunction to be obtained without touching the nitro group (Rao, A. V. R.,J. Chem. Soc. Chem. Commun., 1992, 11, 859).

The intermediates of general formula (XXIX)_(H) can also be prepared,diagram 32.2, starting from intermediates of general formula(XXIX.1)_(H) (R or S) the preparation of which is similar to that of thecompounds of general formula (XXII.1)_(H). Condensation of the alcoholicderivatives of general formula (XXII.2)_(H) on the intermediates ofgeneral formula (XXIX.1)_(H) is also described above. Release of theheterocyclic amine is carried out in the presence of an organic solutionof a strong acid, for example, trifluoroacetic acid.

The amines of general formula (XXIX)_(H), diagram 32.3, are alsoaccessible starting from the substitution of tosylated derivatives ofgeneral formula (XXIX.1)_(H) by the commercial amines of general formula(XXX)_(H). Detachment of the carbamate function from the intermediatesof general formula (XXIX.3)_(H) is carried out as described previously.

The intermediates of general formula (XXIX)_(H) can also be prepared,diagram 32.4, by reaction of the halogenated derivatives of generalformula (IX)_(H) with an alcohol of general formula (XXIX.4)_(H) in thepresence of a base such as for example tBuO⁻K⁺ in an anhydrous solventsuch as THF. The intermediate of general formula (XXIX.5)_(H) thusobtained is then deprotected in a strong acid medium (HCl or TFA).

Synthesis of Intermediates (XXXII)_(H)

The intermediates of general formula (XXXII)_(H) can be prepared,diagram 34.1, by reaction of the halogenated derivatives of generalformula (IX)_(H) with commercial 1-(diphenylmethyl)-3-hydroxyazetidine(XXXII.1)_(H) in the presence of a base such as for example NaH in ananhydrous solvent such as THF. In this case, the nitro group of theintermediate of general formula (XXXII.2)_(H) is reduced in the presenceof SnCl₂, as described previously, in order to produce the intermediateof general formula (XXXII.3)_(H) the amine of which is then protected inthe form of a tButyl carbamate. The detachment of the diphenylmethylprotective group is then carried out in a standard fashion byhydrogenolysis in the presence of Pd(OH)₂ in order to produce theintermediate of general formula (XXXII)_(H).

Unless they are defined differently, all the technical and scientificterms used here have the same meaning as that usually understood by anordinary specialist in the field to which the invention belongs.Similarly, all publications, Patent Applications, Patents and otherreferences mentioned here are incorporated by way of reference.

The following examples are presented to illustrate the above proceduresand should in no way be considered as restricting the scope of theinvention.

EXAMPLES Example 1

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamideHydrochloride: 1

1.1) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide

1.38 g (10 mmoles) of 4-nitroaniline, 2.5 g (10 mmoles) of3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) ofdicyclohexylcarbodiimide are introduced into a 250 ml flask containing20 ml of THF. The reaction medium is agitated for 15 hours at ambienttemperature, and the precipitate which appears is filtered out andrinsed with ethyl acetate After the solution is concentrated underreduced pressure, the residue is diluted in 20 ml of ethyl acetate andthe insoluble part is filtered out. The solvent is eliminated undervacuum and the residue is precipitated from diethyl ether. The solid isrecovered by filtration, rinsed abundantly with diethyl ether in orderto produce a white powder with a yield of 65%. Melting point: 277-278°C.

NMR ¹H (100 MHz, DMSO d6, δ): 10.72 (s, 1H, CONH); 8.30 (m, 4H, Ph-NO₂);7.80 (s, 2H, Ph); 1.60 (s, 18H, 2× tBu).

1.2) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide

In a 250 ml Parr flask, 2.4 g (6.5 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide isdissolved in 50 ml of an absolute ethanol/dichloromethane mixture (1/1)in the presence of 10% Pd/C. The mixture is agitated under 20 PSI ofhydrogen, at 30° C., for one hour. After filtration on celite, thefiltrate is concentrated under vacuum. The evaporation residue is takenup in 25 ml of a 1M HCl solution. The precipitate formed is filtered andrinsed with 50 ml of diethyl ether followed by 50 ml of ethyl acetate.The amine is released from its salt by agitation in a mixture of 50 mlof ethyl acetate and 50 ml of 1M NaOH. After decanting, the organicphase is washed with 25 ml of 1M NaOH and 25 ml of brine. The organicsolution is dried over sodium sulphate, filtered, rinsed andconcentrated to dryness under reduced pressure to produce 1.09 g (49%)of a white powder. Melting point: 220-221° C.

NMR ¹H (100 MHz, DMSO d6, δ): 9.80 (s, 1H, CONH); 7.78 (s, 2H, Ph); 7.05(m, 4H, Ph-NH₂); 5.02 (s, 2H, OH); 1.60 (s, 18H, 2× tBu).

1.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)-amino]phenyl}-benzamideHydrochloride: 1

880 mg (3.08 mmoles) of S-methyl-2-thiophenethiocarboximide hydriodide(Ann. Chim. (1962), 7, 303-337) is introduced into a 100 ml flaskcontaining a solution of 1.05 g (3.08 mmoles) of3,5-bis-(1,1-dimethylethyl)4-hydroxy-N-(4-aminophenyl)-benzamide in 20ml of 2-propanol. After heating at 50° C. for 15 hours, the reactionmedium is concentrated to dryness under vacuum. The residue is taken upin 50 ml of ethyl acetate and 50 ml of a saturated solution of sodiumcarbonate. After decanting, the organic phase is washed successivelywith 50 ml of a saturated solution of sodium carbonate, 50 ml of waterand 50 ml of brine. The organic solution is dried over sodium sulphate,filtered and evaporated under reduced pressure. The crystals obtainedare taken up in diethyl ether, filtered and washed successively withethyl acetate and acetone. 0.77 g of base is obtained with a yield of58%.

The hydrochloride is prepared from 0.77 g (1.71 mmole) of base dissolvedin 60 ml of methanol and salified in the presence of 3.42 ml (3.42mmoles) of a molar solution of HCl in anhydrous diethyl ether. Afteragitating for 30 minutes at ambient temperature, the solvent isevaporated off under vacuum and the residue precipitated in the presenceof diethyl ether. The crystals obtained are filtered and rinsedabundantly with diethyl ether in order to finally produce after drying0.65 g (43%) of a pale yellow powder. Melting point: 290-291° C.

NMR ¹H (400 MHz, DMSO d6δ): 11.55 (s, 1H, NH⁺); 10.40 (s, 1H, CONH);9.83 (s, 1H, NH⁺); 8.85 (s, 1H, NH⁺); 8.21 (m, 2H, thiophene); 7.70 (s,2H, Ph); 7.67 (m, 4H, Ph-NH); 7.60 (s, 1H, OH); 7.40 (m, 1H, thiophene);1.42 (s, 18H, 2× tBu).

IR: ν_(OH): 3624 cm⁻¹, 3430 cm⁻¹; ν_(C═O) (amide): 1653 cm³¹ ¹; ν_(C═N)(amidine): 1587 cm⁻¹.

Example 2

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamideHydrochloride: 2

2.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide

1.88 g (10 mmoles) of p-nitrobenzylamine hydrochloride, 2.5 g (10mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.38 ml (10 mmoles)of triethylamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide areintroduced into a 250 ml flask containing 25 ml of THF. The reactionmedium is agitated for 15 hours at ambient temperature, the precipitatewhich appears is filtered out and rinsed with the minimum quantity ofethyl acetate. After concentration of the solution under reducedpressure, the residue is precipitated from a mixture of ethylacetate/diethyl ether (1/4) and filtered. The crystals are washedabundantly with diethyl ether in order to finally produce, after drying,a white powder with a yield of 74% (2.85 g). Melting point: 230-231° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph-NO₂); 7.69 (s, 2H, Ph); 6.82(m, 1H, NHCO); 5.67 (s, 1H, OH); 4.75 (d, 2H, CH ₂—NHCO, J=6.5 Hz); 1.49(s, 18H, 2× tBu).

2.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamide

In a 250 ml Parr flask, 2.85 g (7.4 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamideis dissolved in 30 ml of an absolute ethanol/dichloromethane mixture(1/1) in the presence of 10% Pd/C. The mixture is agitated under 20 PSIof hydrogen, at 30° C., for one hour. After filtration on celite, thefiltrate is concentrated under vacuum. The evaporation residuecrystallizes spontaneously. It is left to rest overnight, the crystalsare filtered out and rinsed with a mixture of diethyl ether (45 ml) andacetone (5 ml). 1.63 g (62%) of a white powder is obtained. Meltingpoint: 188-189° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.62 (s, 2H, Ph); 6.95 (m, 4H, Ph-NH₂); 6.20(m, 1H, NHCO); 5.58 (s, 1H, OH); 4.50 (d, 2H, CH ₂—NHCO, J=6.5 Hz); 3.70(wide s, 2H, NH₂); 1.47 (s, 18H, 2× tBu).

2.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl-(imino)methyl)-amino]phenyl]methyl}-benzamideHydrochloride: 2

The experimental protocol used is the same as that described forcompound 1, with3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, awhite powder is obtained with a yield of 56%. Melting point: 218-219° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.60 (s, 1H, NH⁺); 9.83 (s, 1H, NH⁺);9.02 (s, 1H, CONH); 8.90 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene); 7.70 (s,2H, Ph); 7.42 (m, 6H, thiophene, Ph-NH, OH); 4.50 (d, 2H, CH ₂—NHCO,J=5.7 Hz); 1.40 (s, 18H, 2× tBu).

IR: ν_(OH): 3624 cm⁻¹, 3424 cm⁻¹; ν_(C═O) (amide): 1644 cm⁻¹; ν_(C═N)(amidine): 1568 cm⁻¹.

Example 3

4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide:3

3.1) 4-acetoxy-3,5-dimethoxy-benzoic Acid

In a 100 ml flask, under a nitrogen atmosphere, 1.50 g (7.57 mmoles) ofsyringic acid is dissolved in 15 ml of dry pyridine. 0.86 ml (9.08mmoles) of acetic anhydride is added dropwise and the mixture isagitated at ambient temperature for 18 hours. The pyridine is evaporatedoff under reduced pressure, the residue is taken up in 25 ml ofdichloromethane and washed with 10 ml of a molar solution of HCl thenwith 2×10 ml of water. The organic phase is dried over sodium sulphate,filtered and evaporated under vacuum. 1.72 g (95%) of a beige powder isobtained. Melting point: 181-183° C.

NMR ¹H (100 MHz, CDCl₃, δ): 8.15 (s, 1H, CO₂H); 7.40 (s, 2H, Ph); 3.90(s, 6H, 2× OCH₃); 2.40 (s, 3H, CH₃).

3.2) 4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide

The experimental protocol used is the same as that described forintermediate 2.1, 4-acetoxy-3,5-dimethoxy-benzoic acid replacing the3,5-di-tert-butyl-4-hydroxy-benzoic acid. A colourless oil is obtainedwith a yield of 28%.

NMR ¹H (100 MHz, DMSO d6, δ): 9.26 (t, 1H, NHCO, J=6.0 Hz); 7.91 (m, 4H,Ph-NO₂); 7.31 (s, 2H, Ph); 4.65 (d, 2H, CH₂, J=6.0 Hz); 3.83 (s, 6H, 2×OCH₃); 2.28 (s, 3H, CH₃).

3.3) 4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide

The experimental protocol used is the same as that described forintermediate 2.2,4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide replacingthe3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A colourless oil is obtained with a yield of 82%. The product is useddirectly in the following stage without additional purification.

3.4) 4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide: 3

The experimental protocol used is the same as that described forcompound 1, with4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide replacingthe 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.The base 3 in the form of a beige powder is obtained with a yield of65%. Melting point: 47-48° C.

NMR ¹H (400 MHz, DMSO d6, δ): 9.08 (wide s, 1H, CONH); 7.75 (m, 1H,thiophene); 7.62 (m, 1H, thiophene); 7.30 (s, 2H, Ph); 7.10 (m, 1H,thiophene); 7.07 (m, 4H, Ph-N); 6.48 (wide s, 2H, NH₂); 4.50 (d, 2H,CH₂, J=4.6 Hz); 3.80 (s, 6H, 2× OCH₃); 2.30 (s, 3H, CH₃).

IR: ν_(C═O) (ester): 1760 cm⁻¹; ν_(C═O) (amide): 1630 cm⁻¹; ν_(C═N)(amidine): 1540 cm⁻¹.

Example 4

3,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide:4

In a 50 ml flask, 1 ml (2 mmoles) of 2N hydrochloric acid is introduceddropwise into a solution of 0.59 g (1 mmole) of compound 3 in 5 ml ofethanol. The reaction medium is agitated for 18 hours at 50° C. Thesolvents are evaporated to dryness, the residue is taken up indichloromethane (5 ml) and washed with molar soda solution (3×5 ml).After drying the organic phase, filtration and concentration to drynessis carried out and the oil obtained is purified by chromatography on asilica gel column (eluant: dichloromethane/methanol: 9/1). The purefractions are collected and after evaporation under vacuum a beigepowder is obtained with a yield of 60%. Melting point: 55-58° C.

NMR ¹H (400 MHz, DMSO d6, δ): 8.92 (s, 1H, OH); 8.84 (m, 1H, CONH); 7.75(m, 1H, thiophene); 7.63 (m, 1H, thiophene); 7.26 (s, 2H, Ph); 7.10 (m,1H, thiophene); 7.05 (m, 4H, Ph-N); 6.50 (s, 2H, NH₂); 4.45 (d, 2H, CH₂,J=5.7 Hz); 3.81 (s, 6H, 2× OCH₃).

IR: ν_(OH): 3300 cm⁻¹. ν_(C═O) (amide): 1630 cm⁻¹; ν_(C═N) (amidine):1590 cm⁻¹.

Example 5

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamideHydriodide: 5

5.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide

2.02 g (10 mmoles) of 4-nitrophenetylamine hydrochloride, 2.5 g (10mmoles) of 3,5-di-tert-butyl-4-hydroxy-benzoic acid, 1.38 ml (10 mmoles)of triethylamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide areintroduced into a 100 ml flask containing 20 ml of THF. The reactionmedium is agitated for 15 hours at ambient temperature, the precipitatewhich appears is filtered out and rinsed with ethyl acetate. Afterconcentration of the filtrate under reduced pressure, the residue isprecipitated from diethyl ether. The solid is recovered by filtrationand rinsed with diethyl ether. A white powder is obtained with a yieldof 73%. Melting point: 204-206° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.52 (s, 2H, Ph); 6.85 (m, 4H, Ph-NO₂); 6.02(m, 1H, NHCO); 3.62 (m, 2H, CH ₂—NHCO); 2.82 (m, 2H, CH ₂-Ph-NO₂); 1.48(s, 18H, 2× tBu).

5.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide

The experimental protocol used is the same as that described forintermediate 2.2,3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A white powder is obtained with a yield of 76%. Melting point: 193-195°C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.80 (m, 4H, Ph-NH₂); 7.55 (s, 2H, Ph); 6.10(m, 1H, NHCO); 5.55 (s, 1H, OH); 3.75 (m, 2H, CH ₂—NHCO); 3.10 (m, 2H,CH ₂-Ph-NH₂); 1.50 (s, 18H, 2× tBu).

5.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamideHydriodide: 5

0.78 g (2.74 mmoles) of S-methyl-2-thiophene-thiocarboximide hydriodide(Ann. Chim. (1962), 7, 303-337) is introduced into a 50 ml flaskcontaining 1.01 g (2.74 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamidedissolved in 20 ml of 2-propanol. The reaction medium is heated at 40°C. for 4 hours. The solvent is evaporated off under vacuum and theresidue is precipitated in the presence of 50 ml of a water/ethylacetate mixture (1/1). The crystals formed are filtered out and washedsuccessively with ethyl acetate and diethyl ether. After drying, a paleyellow powder is obtained with a yield of 68%. Melting point: 185-186°C.

NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (s, 1H, NH⁺); 8.88 (s, 1H, NH⁺); 8.40(s, 1H, CONH); 8.12 (m, 2H, thiophene); 7.60 (s, 2H, Ph); 7.42 (m, 6H,thiophene, Ph-NH, OH); 3.52 (d, 2H, CH ₂—NHCO, J=5.9 Hz); 2.90 (m, 2H,CH ₂-Ph-NH); 1.40 (s, 18H, 2× tBu).

IR: ν_(OH): 3624 cm⁻¹, 3423 cm⁻¹; ν_(C═O) (amide): 1636 cm⁻¹; ν_(C═N)(amidine): 1569 cm⁻¹.

Example 6

4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide Fumarate: 6

6.1) 4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide

The experimental protocol used is the same as that described forintermediate 5.1, with 4-acetoxy-3,5-dimethoxy-benzoic acid(intermediate 3.1) replacing the 3,5-di-tert-butyl-4-hydroxy benzoicacid. A colourless oil is obtained with a yield of 70%. The product isused directly in the following stage.

6.2) 4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide

The experimental protocol used is the same as that described forintermediate 2.2, with4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacingthe3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A colourless oil is obtained with a quantitative yield. The product isused directly in the following stage without additional purification.

6.3)4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]-phenyl]ethyl}-benzamide Fumarate: 6

The experimental protocol used to produce the free base is the same asthat described for the synthesis of compound 1, with4-acetoxy-3,5-dimethoxy-N- [2-(4-aminophenyl)ethyl]-benzamide replacingthe 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.

The product of the reaction is salified in the presence of an equimolarquantity of fumaric acid in ethanol under reflux. Compound 6 is obtainedin the form of a beige powder with a yield of 74%. Melting point:178-180° C.

NMR ¹H (400 MHz, DMSO d6, δ): 8.60 (m, 1H, CONH); 7.75 (m, 1H,thiophene); 7.64 (d, 1H, thiophene, J=5.0 Hz); 7.20 (s, 2H, Ph); 7.11(t, 1H, thiophene, J=9.0 Hz); 7.02 (m, 4H, Ph-N); 6.61 (s, 2H, CH═CHfumarate); 3.81 (s, 6H, 2× OCH₃); 3.50 (q, 2H, CH₂-N, J=6.5 Hz); 2.82(t, CH ₂-Ph, J=7.0 Hz); 2.27 (s, 3H, CH₃).

IR: ν_(C═O) (ester): 1750 cm⁻¹; ν_(C═O) (amide): 1640 cm⁻¹; ν_(C═N)(amidine): 1550 cm⁻¹.

Example 7

3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamideHydrochloride: 7

In a 50 ml flask, 1.40 ml (2.80 mmoles) of a solution of 2N hydrochloricacid is added dropwise to a solution of 0.64 g (1.37 mmoles) of compound6 in the form of the free base in 5 ml of ethanol. The reaction mediumis agitated for 18 hours at 50° C. The solvents are evaporated todryness and the evaporation residue is precipitated from a mixture of 5ml of a 2N solution of soda and 10 ml of dichloromethane. Afterfiltration, the solid is taken up in (4N) hydrochloric ethanol. A lightprecipitate is then eliminated. The solvent is evaporated under reducedpressure and the residue taken up in acetone. Product 7 precipitated inthe form of the hydrochloride is obtained with a yield of 58%. Meltingpoint: 164-167° C.

NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (wide s, 1H, NH⁺); 8.90 (s, 2H, NH⁺,OH); 8.54 (m, 1H, CONH); 8.18 (s, 1H, thiophene); 8.16 (s, 1H,thiophene); 7.40 (m, 4H, Ph-N); 7.21 (s, 2H, Ph); 7.11 (m, 1H,thiophene); 3.81 (s, 6H, 2× OCH₃); 3.51 (q, 2H, CH₂—N, J 7.0 Hz); 2.92(t, CH ₂-Ph, J 7.0 Hz).

IR: ν_(OH): 3300 cm⁻¹; ν_(C═O) (amide): 1620 cm⁻¹; ν_(C═N) (amidine):1560 cm⁻¹.

Example 8

3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamideHemi-fumarate: 8

8.1) 3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide

2 g (11.5 mmoles) of gallic acid, 2.5 g (11.5 mmoles) of4-nitrophenetylamine hydrochloride, 1.8 g (11.5 mmoles) of hydrated1-hydroxybenzotriazole, 2.25 g (11.5 mmoles) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3.3 ml(23 mmoles) of triethylamine are introduced into a 100 ml flaskcontaining 30 ml of anhydrous DMF. The orange-coloured solution obtainedis agitated at 20° C. for 20 hours and diluted in a mixture ofdichloromethane (50 ml) and water (30 ml). After decanting, the organicphase is washed with a molar solution of hydrochloric acid (20 ml) andwith water (3×20 ml) until neutrality is achieved. After drying theorganic phase over magnesium sulphate, followed by filtration andconcentration under vacuum, the residue is purified on a silica gelcolumn (eluant: dichloromethane/methanol: 9/1). The expected product isobtained in the form of a colourless oil with a yield of 42% (1.57 g).

NMR ¹H (100 MHz, DMSO d6, δ): 8.95 (m, 3H, 3× OH); 7.85 (m, 4H, Ph-NO₂);6.80 (s, 2H, Ph); 3.36 (m, 2H, CH₂-N); 2.97 (t, 2H, CH ₂-Ph, J=6.0 Hz).

8.2) 3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide

The experimental protocol used is the same as that described forintermediate 2.2, with3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A beige powder is obtained with a yield of 89%. Melting point: 167-169°C.

NMR ¹H (100 MHz, DMSO d6, δ): 8.80 (m, 3H, OH); 8.07 (t, 1H, NHCO, J=5.0Hz); 6.81 (s, 2H, Ph); 6.68 (m, 4H, Ph-NH₂); 3.28 (m, 2H, CH₂—N); 2.60(t, 2H, CH ₂-Ph, J=7.0 Hz).

8.3)3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamideHemi-fumarate: 8

The experimental protocol used is the same as that described forcompound 1, with 3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Base8 is obtained in the form of a powder which is salified, by heatingunder reflux with ethanol, in the presence of one equivalent of fumaricacid. The salt crystallizes spontaneously at 20° C. After filtration andwashing with ethanol the expected product is obtained in the form of abeige powder with a yield of 53%. Melting point: 245-246° C.

NMR ¹H (400 MHz, DMSO d6, δ): 8.85 (m, 3H, 3× OH); 8.14 (t, 1H, NHCO,J=5.0 Hz); 7.73 (s, 1H, thiophene); 7.60 (d, 1H, thiophene, J=5.0 Hz);7.16 (s, 2H, Ph); 7.09 (t, 1H, thiophene, J=4.0 Hz); 6.80 (m, 4H, Ph-N);6.59 (wide s, 2H, 1/2-CH═CH, NH); 3.41 (m, 3H, CH₂—N⁺NH); 2.76 (t, 2H,CH₂, J=7.5 Hz).

IR: ν_(OH): 3300 cm⁻¹; ν_(V═O) (amide): 1620 cm⁻¹; ν_(C═N) (amidine):1590 cm⁻¹.

Example 9

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 9

9.1)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol

2.07 g (10 mmoles) of 1-(4-nitrophenyl)piperazine, 2.5 g (10 mmoles) of3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) ofdicyclohexylcarbodiimide are introduced into a 100 ml flask containing25 ml of DMF. The reaction medium is agitated for 15 hours at ambienttemperature, the precipitate which appears is filtered out and rinsedwith ethyl acetate. After concentration of the filtrate under reducedpressure, the residue is diluted in 20 ml of ethyl acetate and a newinsoluble is eliminated by filtration. The solvent is evaporated offunder vacuum and the residue is precipitated from diethyl ether. Thesolid is filtered, rinsed with 2×20 ml of ethyl acetate in order toobtain a yellow powder with a yield of 89%. Melting point: 159.5-160.5°C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.58 (m, 4H, Ph-NO₂); 7.30 (s, 2H, Ph); 5.50(s, 1H, OH); 3.85 (m, 4H, piperazine); 3.55 (m, 4H, piperazine); 1.46(s, 18H, 2× tBu).

9.2)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenol

In a 250 ml Parr flask, 2.19 g (5.0 mmoles) of intermediate 9.1 isdissolved in 50 ml of absolute ethanol in the presence of 10% Pd/C. Themixture is agitated under 20 PSI of hydrogen, at 30° C., for one hour.After filtration on celite, the filtrate is concentrated under vacuum.The evaporation residue is taken up in 25 ml of diethyl ether, filteredand rinsed with 2×20 ml of diethyl ether. A pale pink powder is obtainedwith a yield of 82%. Melting point: 221-222° C.

NMR¹H (100 MHz, CDCl₃, δ): 7.30 (s, 2H, Ph); 6.75 (m, 4H, Ph-NH₂); 5.45(s, 1H, OH); 3.80 (m, 4H, piperazine); 3.10 (m, 4H, piperazine); 1.49(s, 18H, 2× tBu).

9.3)N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideHydrochloride: 9

The experimental protocol used is the same as that described forcompound 1, with2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftertreatment with a molar solution of HCl in anhydrous diethyl ether, abeige powder is obtained with a yield of 75%. Melting point: 235-236° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.45 (s, 1H, NH⁺); 9.78 (s, 1H, NH⁺);8.75 (s, 1H, NH⁺); 8.19 (m, 2H, thiophene); 7.29 (m, 5H, Ph-N,thiophene); 7.10 (s, 2H, Ph); 5.60 (wide s, 1H, OH); 3.70 (m, 4H,piperazine); 3.30 (m, 4H, piperazine); 1.40 (s, 18H, 2× tBu).

IR: ν_(OH): 3633 cm⁻¹, 3433 cm⁻¹; ν_(C═O) (amide): 1617 cm⁻¹; ν_(C═N)(amidine): 1590 cm⁻¹.

Example 10

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 10

10.1) 2,6-bis-(1,1-dimethylethyl)-4-bromomethylphenol

In a 250 ml three-necked flask under a nitrogen atmosphere, 2.36 g (10mmoles) of 3,5 di-tert-butyl-4-hydroxybenzylic alcohol is dissolved in25 ml of anhydrous THF. The solution is cooled down using an ice bathbefore the dropwise addition of 0.95 ml (10 mmoles) of phosphorustribromide diluted with 25 ml of anhydrous THF. After 15 minutes ofagitation at 0° C., the solution is diluted with 100 ml ofdichloromethane and washed with 3×30 ml of water followed by 30 ml ofbrine. The organic phase is dried over sodium sulphate, filtered andconcentrated under vacuum to produce a brown oil which is used directlyin the following stage.

10.2)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-methyl}-phenol

In a 100 ml flask containing a solution of 2.99 g (10 mmoles) of2,6-bis-(1,1-dimethylethyl)-4-bromomethylphenol in 30 ml of DMF, 1.38 g(10 mmoles) of potassium carbonate and 2.07 g (10 mmoles) of1-(4-nitrophenyl)piperazine are added successively. After agitation fortwo hours at ambient temperature, the reaction medium is diluted with150 ml of dichloromethane and washed successively with 3×40 ml of waterfollowed by 40 ml of brine. The organic solution is dried over sodiumsulphate, filtered and concentrated under reduced pressure. The brownresidue obtained is purified on a silica gel column (eluant: petroleumether (B.p. 40-70° C.)/ethyl acetate: 8/2). After concentration of thepure fractions, 2.31 g (54%) of a brown powder is obtained. Meltingpoint: 177.5-178.5° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.50 (m, 4H, Ph-NO₂); 7.12 (s, 2H, Ph); 5.19(s, 1H, OH); 3.50 (s, 2H, CH ₂-Ph); 3.49 (m, 4H, piperazine); 2.60 (m,4H, piperazine); 1.49 (s, 18H, 2× tBu).

10.3)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-methyl}-phenol

The experimental protocol used is the same as that described forintermediate 9.2, with2,6-bis-(1,1-dimethylethyl)-4-{[[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl]-methyl}-phenol replacing the2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol.A pale pink powder is obtained with a yield of 75%. Melting point:152-154° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.12 (s, 2H, Ph); 6.78 (m, 4H, Ph-NH₂); 3.59(s, 2H, CH₂-Ph); 3.18 (m, 4H, piperazine); 2.70 (m, 4H, piperazine);1.47 (s, 18H, 2× tBu).

10.4)N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideHydrochloride: 10

0.43 g (1.5 mmole) of S-methyl-2-thiophene-thiocarboximide hydriodide(Ann. Chim. (1962), 7, 303-337) is introduced into a 100 ml flaskcontaining 0.59 g (1.5 mmole) of intermediate 10.3 in 20 ml of2-propanol. After heating under reflux for 15 hours, the reaction mediumis concentrated to dryness under vacuum. The residue is purified on asilica gel column (eluant: dichloromethane/ethanol: 90/10). The purefractions are concentrated under vacuum and the evaporation residue issalified in the presence of a molar solution of HCl in anhydrous diethylether. A pale yellow powder is obtained with a yield of 40%. Meltingpoint: 234-236° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.60 (s, 1H, NH⁺); 11.40 (s, 1H, NH⁺);9.75 (s, 1H, NH⁺); 8.70 (s, 1H, NH⁺); 8.17 (m, 2H, thiophene); 7.39 (s,2H, Ph); 7.38 (m, 1H, thiophene); 7.24 (m, 5H, Ph-N, OH); 4.26 (d, 2H,CH₂-Ph, J=4.6 Hz); 3.90 (m, 2H, piperazine); 3.35 (m, 4H, piperazine);3.15 (m, 2H, piperazine); 1.41 (s, 18H, 2× tBu).

IR: ν_(OH): 3624 cm⁻¹, 3418 cm⁻¹; ν_(C═N) (amidine): 1610 cm⁻¹.

Example 11

N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideHydrochloride: 11

11.1) 2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-phenol

In a 100 ml flask, 0.99 g (5 mmoles) of syringic acid, 0.74 g (5.5mmoles) of hydroxybenzotriazol, 1.10 g (5.5 mmoles) ofdicyclohexylcarbodiimide and 1.04 g (5 mmoles) of1-(4-nitrophenyl)piperazine are dissolved in 10 ml of DMF. Afteragitation at ambient temperature for 7 hours, the mixture is filteredand the precipitate rinsed with 20 ml of DMF followed by 100 ml ofchloroform. 2 g of a yellow powder is obtained, containing approximately20% of dicyclohexylurea. The product is used as it is in the followingstage.

NMR ¹H (100 MHz, DMSO d6, δ): 7.69 (m, 4H, Ph-NO₂); 6.88 (s, 2H, Ph);5.72 (m, 1H, OH); 3.91 (s, 6H, 2× OCH₃); 3.75 (m, 4H, piperazine); 3.49(m, 4H, piperazine).

11.2) 2,6-dimethoxy-4-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-phenol

In a 250 ml Parr flask, 2 g of intermediate 11.1 is dissolved in 40 mlof absolute ethanol/DMSO (1/3) in the presence of 10% Pd/C. The mixtureis agitated under 20 PSI of hydrogen, at 25° C., for 15 hours. Afterfiltration on celite, the filtrate is concentrated under vacuum. Thebrown evaporation residue is taken up in 50 ml of ethyl acetate, theprecipitate formed is eliminated by filtration, rinsed with 20 ml ofethyl acetate and the filtrate extracted with 2×25 ml of a molarsolution of HCl. The aqueous phase is alkalinized by the addition ofpowdered sodium carbonate and extracted with 2×50 ml of ethyl acetate.The organic solution is dried over sodium sulphate, filtered andconcentrated under vacuum. The powder obtained is taken up in 20 ml ofdiethyl ether containing 3 ml of methanol, filtered and rinsed usingdiethyl ether. 400 mg (22% over the two stages) of brown crystals areobtained. Melting point: 182-183° C.

NMR ¹H (100 MHz, DMSO d6, δ): 6.80 (s, 2H, Ph); 6.74 (m, 4H, Ph-NH₂);4.80 (m, 2H, NH₂); 3.91 (s, 6H, 2× OCH₃); 3.77 (m, 4H, piperazine); 3.08(m, 4H, piperazine).

11.3)N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideHydrochloride: 11

0.32 g (1.13 mmole) of S-methyl-2-thiophenethiocarboximide hydriodide(Ann. Chim. (1962), 7, 303-337) is introduced into a 100 ml flaskcontaining a solution of 0.4 g (1.13 mmole) of intermediate 11.2 in 10ml of 2-propanol. After heating at 50° C. for 15 hours, the reactionmedium is concentrated to dryness under vacuum. The evaporation residueis then taken up in 100 ml of an ethyl acetate/saturated solution ofsodium carbonate mixture (1/1). A precipitate appears which is filteredand rinsed successively with 20 ml of water, 20 ml of ethyl acetate and50 ml of ether. The base obtained is salified in the presence of a molarsolution of HCl in anhydrous diethyl ether. After filtration, rinsingwith 10 ml of acetone and drying, 0.12 g (20%) of a pale yellow powderis obtained. Melting point: 184-185° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.47 (s, 1H, NH⁺); 9.78 (s, 1H, NH⁺);8.76 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene); 7.37 (m, 1H, thiophene);7.28 (m, 4H, Ph-N); 6.74 (s, 2H, Ph); 4.27 (wide s, 1H, OH); 3.80 (s,6H, 2× OCH₃); 3.70 (m, 4H, piperazine); 3.33 (m, 4H, piperazine).

IR: ν_(OH): 3423 cm⁻¹; ν_(C═O)(amide): 1610 cm⁻¹; ν_(C═N) (amidine):1587 cm⁻¹.

Example 12

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide Hydrochloride:12

12.1)3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide

In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazol isadded to a solution of 2.5 g (10 mmoles) of Trolox® in 25 ml of THF.After agitation at ambient temperature for one hour, a solution of4-nitroaniline in 20 ml of THF is added dropwise. Agitation is continuedfor 15 hours and the solvent is evaporated off under vacuum. The residueis diluted in 50 ml of dichloromethane and washed successively with 25ml of a molar solution of hydrochloric acid, 25 ml of water and 25 ml ofbrine. The organic phase is dried over sodium sulphate, filtered andconcentrated under reduced pressure. The oil obtained is purified on asilica gel column (eluant: petroleum ether (B.p. 40-70° C.)/ethylacetate: 7/3). After concentration of the pure fractions, a pale yellowpowder is obtained with a yield of 77%. Melting point: 150-151° C.

NMR ¹H (100 MHz, CDCl₃, δ): 8.68 (s, 1H, CONH); 7.91 (m, 4H, Ph); 4.59(s, 1H, OH); 2.95-0.87 (m, 16H, Trolox®).

12.2)3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamide

The experimental protocol used is the same as that described forintermediate 9.2, with3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide replacing the2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol. The product of the reaction is purifiedon a silica gel column (eluant: petroleum ether (B.p. 40-70° C.)/ethylacetate: 6/4). The pure fractions are collected, after evaporation ofthe solvent under vacuum, a colourless oil is obtained with a yield of45%.

NMR ¹H (100 MHz, CDCl₃, δ): 8.19 (s,1H, CONH); 7.00 (m, 4H, Ph); 4.59(s, 1H, OH); 3.65 (wide s, 2H, NH₂); 2.95-0.87 (m, 16H, Trolox®).

12.3)3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[2-thienyl(iminomethyl)amino]phenyl}-2H-1-benzopyran-2-carboxamideHydrochloride: 12

The experimental protocol used is the same as that described forcompound 1, with3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.Melting point: 279-280° C.

NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (s, 1H, NH⁺); 9.50 (s, 1H, NH⁺); 8.73(s, 1H, NHCO); 8.18 (m, 2H, thiophene); 7.60 (s, 1H, OH); 7.59 (m, 4H,Ph); 7.36 (m, 1H, thiophene); 2.60-1.57 (m, 16H, Trolox®).

IR: ν_(OH): 3236 cm⁻¹; ν_(C═O) (amide): 1683 cm⁻¹; ν_(C═N) (amidine):1577 cm⁻¹.

Example 13

N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 13

13.1)3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol

In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazole isadded to a solution of 2.5 g (10 mmoles) of Trolox® in 25 ml of THF.After one hour of agitation at ambient temperature, a solution of1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitationis continued for 15 hours, the reaction medium is then concentratedunder vacuum. The evaporation residue is dissolved in 50 ml ofdichloromethane and washed successively with 3×25 ml of water and 25 mlof brine. The organic phase is dried over sodium sulphate, filtered andconcentrated under reduced pressure. The oil obtained is precipitatedfrom 30 ml of a (95/5) ethyl acetate/methanol mixture, the solid isfiltered out and washed with 2×20 ml of ethyl acetate. A pale yellowpowder is obtained with a yield of 79%. Melting point: 199-200° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.45 (m, 4H, Ph); 4.41-3.35 (m, 8H,piperazine); 2.95-1.25 (m, 16H, Trolox®).

13.2)3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol

The experimental protocol used is the same as that described forintermediate 2.2, with3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.The product of the reaction is purified on a silica gel column (eluant:dichloromethane/methanol: 9/1). The pure fractions are collected toproduce, after evaporation of the solvent under vacuum, a brown oil witha yield of 66%.

NMR ¹H (100 MHz, CDCl₃, δ): 6.70 (m, 4H, Ph); 4.15-2.97 (m, 8H,piperazine); 2.80-0.90 (m, 18H, Trolox®).

13.3)N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 13

The experimental protocol used is the same as that described for thecompound 1, with3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-amino-phenyl)-benzamide.However, the reaction is slower and requires 15 hours of heating. Thebase obtained after extraction is purified on a silica gel column(eluant: petroleum ether (B.p. 40-70° C.)/ethyl acetate: 3/7). The purefractions are concentrated under vacuum and the evaporation residue issalified in the presence of a molar solution of HCl in anhydrous diethylether. A yellow powder pale is obtained with a yield of 40%. Meltingpoint: 210-211° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (s, 1H, NH⁺); 9.79 (s, 1H, NH⁺);8.69 (s, 1H, NH⁺); 8.19 (m, 2H, thiophene); 7.38 (m, 1H, thiophene);7.20 (m, 4H, Ph); 4.58 (wide s, 1H, OH); 4.11 (m, 2H, piperazine); 3.61(m, 2H, piperazine); 3.19 (m, 4H, piperazine); 2.62-1.55 (m, 16H,Trolox®).

IR: ν_(OH): 3410 cm⁻¹; ν_(C═O) (amide): 1642 cm⁻¹; ν_(C═N) (amidine):1613 cm⁻¹.

Example 14

N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide:14

14.1)1-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine

In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazole isadded to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-aceticacid in 10 ml of THF. After one hour of agitation at ambienttemperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMFis added dropwise. Agitation is continued for 15 hours. The reactionmedium is then concentrated under vacuum and the evaporation residue isprecipitated from 50 ml of an ethyl acetate/water mixture (1/1). Afterfiltration, the solid is rinsed successively with 50 ml of water, 50 mlof ethyl acetate and 50 ml of dichloromethane. After drying undervacuum, a yellow powder is obtained with a yield of 91%. Melting point:239-240° C.

NMR ¹H (100 MHz, DMSO d6, δ): 10.90 (m, 1H, NH); 7.63 (m, 4H, Ph-NO₂);7.40-7.15 (m, 3H, indol); 6.87 (dd, 1H indol, J_(ortho)=8.7 Hz,J_(meta)=2.8 Hz); 3.90 (s, 2H, CH₂—CO); 3.88 (s, 3H, OCH₃); 3.79 (m, 4H,piperazine); 3.50 (m, 4H, piperazine).

14.2) 1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine

In a 250 ml Parr flask, 1 g (2.53 mmoles) of intermediate 14.1 isdissolved in 30 ml of DMSO in the presence of 10% Pd/C. The mixture isagitated under 20 PSI of hydrogen, at 25° C., for 7 hours. Afterfiltration on celite, the filtrate is concentrated under vacuum. Theevaporation residue is diluted in 50 ml of ethyl acetate and washed with3×50 ml of water. The organic phase is then extracted with 2×25 ml of amolar solution of HCl. After the acid solution is washed with 2×25 ml ofethyl acetate, it is alkalinized using sodium carbonate in powder form.Once the product is re-extracted using 2×50 ml of ethyl acetate, theorganic solution is dried over sodium sulphate, filtered and the solventis evaporated off under vacuum. The residue is purified on a silica gelcolumn (eluant: dichloromethane/methanol: 98/2). The pure fractions arecollected and after evaporation of the solvent under reduced pressure,0.39 g of a pale yellow powder is obtained with a yield of 46%. Meltingpoint: 119-120° C.

NMR ¹H (100 MHz, CDCl₃, δ): 8.32 (s, 1H, indolic NH); 7.27-6.80 (m, 4H,indole); 6.69 (m, 4H, Ph-NH₂); 3.82 (s, 3H, OCH₃); 3.80 (s, 2H, CH₂—CO);3.80 (m, 2H, piperazine); 3.62 (m, 2H, piperazine); 3.48 (s, 2H, NH₂);2.90 (m, 4H, piperazine).

14.3) N-{4-[4-[(5methoxy-1H-indole-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide:14

The experimental protocol used is the same as that described for thecompound 1 with 1-[(5methoxy-1H-indole-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazinereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Theexpected product is isolated in the form of the free base with a yieldof 20% (pale yellow powder). Melting point: 221-222° C.

NMR ¹H (400 MHz, DMSO d6, δ): 10.78 (s, 1H, indolic NH); 7.72 (m, 1H,thiophene); 7.59 (m, 1H, thiophene); 7.22 (d, 1H, indole, J=8.7 Hz);7.19 (m, 1H, thiophene); 7.09 (m, 2H, indole); 6.82 (m, 4H, Ph); 6.72(m, 1H indole); 6.35 (s, 2H, NH₂); 3.80 (s, 2H, CH₂); 3.73 (s, 3H, CH₃);3.62 (m, 4H, piperazine); 2.95 (m, 4H, piperazine).

IR: ν_(OH): 3414 cm⁻¹; ν_(C═O) (amide): 1628 cm⁻¹; ν_(C═N) (amidine):1590 cm⁻¹.

Example 15

N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamideFumarate: 15

15.1)2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-nitrophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol

The experimental protocol used is the same as that described forintermediate 11.1, with 3,5-di-tert-butyl-4-hydroxycinnamic acidreplacing the syringic acid. An oil is obtained with a yield of 60%.

NMR ¹H (100 MHz, CDCl₃, δ): 7.71 (d, 1H, C═CH, J=15.0 Hz); 7.51 (m, 4H,Ph-NO₂); 7.38 (s, 2H, Ph); 6.69 (d, 1H, HC═C, J=15.0 Hz); 5.50 (s, 1H,OH); 3.88 (m, 4H, piperazine); 3.53 (m, 4H, piperazine); 1.47 (s, 18 H,2× tBu).

15.2)2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol

In a 50 ml flask equipped with a refrigerant, 0.5 g (1 mmole) ofintermediate 15.1 is dissolved in 5 ml of concentrated hydrochloric acidand 5 ml of absolute ethanol. The mixture is cooled down to 0° C. and1.69 g (7.5 mmoles) of tin chloride (dihydrate) is added in severalportions. After this addition, the reaction medium is heated underreflux for 30 minutes. The solvents are then evaporated off undervacuum, the residue is taken up in 15 ml of water, neutralized with 2Nsoda and diluted with 20 ml of dichloromethane. The precipitate obtainedis filtered on celite and the filtrate is decanted. The organic phase isdried over sodium sulphate, filtered and concentrated under reducedpressure to produce 0.3 g (67%) of a yellow oil.

NMR ¹H (100 MHz, CDCl₃, δ): 7.66 (d, 1H, C═CH, J=15.0 Hz); 7.37 (s, 2H,Ph); 6.75 (m, 4H, Ph-NH₂); 6.30 (d, 1H, HC═C, J=15.0 Hz); 5.46 (s, 1H,OH); 3.80 (m, 4H, piperazine); 3.06 (m, 4H, piperazine); 1.46 (s, 18 H,2× tBu).

15.3)N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxy-phenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamideFumarate: 15

The experimental protocol used is the same as that described forcompound 1, with2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.

The product of the reaction is salified in the presence of an equimolarquantity of fumaric acid in ethanol under reflux. Compound 15 isobtained in the form of a yellow powder with a yield of 22%. Meltingpoint: 170.5-173° C.

NMR ¹H (400 MHz, DMSO d6, δ): 7.77 (s, 1H, thiophene); 7.67 (d, 1H,thiophene, J=5.0 Hz); 7.48 (d, 1H, C═CH, J=15.0 Hz); 7.39 (s, 2H, Ph);7.34 (wide s, 1H, OH); 7.13 (t, 1H, thiophene, J=4.0 Hz); 7.05 (d, 1H,HC═C, J=15.0 Hz); 6.92 (m, 4H, Ph-N); 6.60 (s, 2H, CH═CH fumarate); 3.78(m, 4H, piperazine); 3.13 (m, 4H, piperazine); 1.41 (s, 18 H, 2× tBu).

IR: ν_(OH): 3619 cm⁻¹, 3300 cm⁻¹; ν_(C═O) (amide): 1640 cm⁻¹; ν_(C═C):1600 cm⁻¹; ν_(C═N) (amidine): 1570 cm⁻¹.

Example 16

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamideHydrochloride: 16

16.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide

The experimental protocol used is the same as that described forintermediate 2.1, with 3-nitrobenzylamine hydrochloride replacing the4-nitrobenzylamine hydrochloride. A white powder is obtained with ayield of 63%. Melting point: 210-211° C.

NMR ¹H (100 MHz, DMSO, δ): 9.12 (m, 1H, NH); 8.25 (m, 2H, Ph-NO₂); 7.80(m, 4H, Ph-NO₂+Ph-OH); 7.60 (wide s, 1H, OH); 4.68 (d, 2H, CH₂, J=6 Hz);1.55 (s, 18H, 2 × tBu).

16.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamide

In a 250 ml Parr flask, 2.40 g (6.2 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamideis dissolved in 45 ml of an absolute ethanol/THF mixture (1/2) in thepresence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen,at 30° C., for three hours. After filtration on celite, the filtrate isconcentrated to dryness and the residue is purified on a silica column(eluant: heptane/ethyl acetate: 60/40). The pure fractions are collectedand concentrated under reduced pressure to produce 0.94 g (45%) of awhite powder. Melting point: 171-172° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.20 (m, 2H, Ph-NH₂); 6.70 (m, 4H,Ph-NH₂+Ph-OH); 6.34 (m, 1H, NH); 5.55 (s, 1H, OH); 4.56 (d, 2H, CH₂, J=6Hz); 3.70 (wide s, 2H, NH₂); 1.49 (s, 18H, 2×tBu).

16.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl-(imino)methyl)-amino]phenyl]methyl}-benzamideHydrochloride: 16

The experimental protocol used is the same as that described forcompound 1, with3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in an acetone/anhydrousmethanol mixture, a pale yellow powder is obtained with a yield of 50%.Melting point: 226-227° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.71 (s, 1H, NH⁺); 9.93 (s, 1H, NH⁺);9.10 (s, 1H, CONH); 9.00 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene); 7.70 (s,2H, Ph); 7.42 (m, 6H, thiophene, Ph-NH, OH); 4.50 (d, 2H, CH ₂—NHCO,J=5.4 Hz); 1.40 (s, 18H, 2×tBu).

IR: ν_(OH): 3420 cm^(−1;) ν_(C═O) (amide): 1639 cm^(−1:) ν_(C═N)(amidine): 1578 cm⁻¹.

Example 17

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-ureaHydrochloride: 17

17.1) 4-amino-2,6-bis-(1,1-dimethylethyl)-phenol

In a 250 ml Parr flask, 3.6 g (14 mmoles) of4-nitro-2,6-bis-(1,1-dimethylethyl)-phenol (J. Org. Chem. (1968), 33(1), 223-226) is dissolved in 60 ml of a (2/1) mixture of ethanol anddichloromethane in the presence of a catalytic quantity of 10% Pd/C. Themixture is agitated for 2 hours, at 20° C., under 20 PSI of hydrogen.After filtration on celite, the filtrate is concentrated to drynessunder reduced pressure. The reddish-brown powder obtained is suspendedin heptane (30 ml), filtered and rinsed with the same volume of heptane.The expected product is obtained in the form of an salmon pink powderwith a yield of 50% (1.56 g). Melting point: 123-124° C.

NMR 1H (100 MHz, CDCl₃, δ): 6.60 (s, 2H, Ph); 4.65 (wide s, 1H, OH);3.15 (wide s, 2H, NH₂); 1.42 (s, 18H, 2× tBu).

17.2) 4-nitrophenylacetic Acid Chloride

3.75 ml (7.5 mmoles) of a 2M solution of oxalyl chloride indichloromethane is added at 20° C. to a solution of 0.9 g (5 mmoles) of4-nitrophenylacetic acid in a mixture composed of 10 ml ofdichloromethane and 0.5 ml of DMF. After agitation for 30 minutes, thesolution is concentrated under vacuum. The yellow oil obtained is usedwithout additional purification in the following stage.

17.3) 4-nitrobenzylisocyanate

The chloride of 4-nitrophenylacetic acid in solution in dry acetone (7.5ml) is slowly added to an aqueous solution of 0.75 g (11.5 mmoles) ofsodium azide, cooled down to 0° C. Agitation of the medium is maintainedfor one hour after the addition is completed, at 0-5° C. The reactionmedium is then diluted with 30 ml of chloroform, decanted and theorganic phase washed with water (20 ml) followed by a saturated solutionof sodium chloride (20 ml). After drying over sodium sulphate, theorganic solution is filtered and partly concentrated (≈20 ml) undervacuum. This solution of the acylazide in chloroform is then heated,under reflux, for one hour. The isocyanate obtained is used directly, insolution, in the following stage.

17.4)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-urea

1.1 g (5 mmoles) of 4-amino-2,6-bis-(1,1-dimethylethyl)-phenol is addedin one portion to the isocyanate solution (intermediate 17.3)(theoretically 5 mmoles) in 20 ml of chloroform. After agitation for 2hours at 20° C., the precipitate which appears is filtered out andrinsed with chloroform (2×20 ml). A yellow powder is obtained with ayield of 72%. Melting point: 240-241° C.

NMR ¹H (100 MHz, DMSO d6, δ): 8.60 (s, 1H, NH-Ph); 8.01 (m, 4H, Ph-NO₂);7.30 (s, 2H, Ph-OH); 6.77 (m, 1H, NH—CH₂); 6.71 (s, 1H, OH); 4.52 (d,2H, CH₂, J=5.5 Hz); 1.49 (s, 18H, 2× tBu).

17.5)N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea

In a 100 ml autoclave, 0.55 g (1.38 mmole) ofN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-ureais dissolved in a 2/1 mixture of ethanol and ethyl acetate, in thepresence of 10% Pd/C. After hydrogenation for one and a half hours at20° C., under 20 PSI, the mixture is filtered on celite and the filtrateis concentrated under vacuum. The evaporation residue is diluted in 20ml of diethyl ether and the expected product crystallizes spontaneously.The crystals are filtered out and rinsed with 20 ml of diethyl ether. Awhite powder is obtained with a yield of 60% (0.31 g). Melting point:194-195° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.08 (s, 2H, Ph-OH); 6.87 (m, 4H, Ph-NH₂);6.15 (s, 1H, NH-Ph); 5.14 (s, 1H, OH); 4.89 (m, 1H, NH—CH₂); 4.41 (d,2H, CH₂, J=5.5 Hz); 3.65 (wide s, 2H, NH₂); 1.40 (s, 18H, 2× tBu).

17.6)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[2-thienyl(imino-methyl)amino]phenyl}methyl}-ureaHydrochloride: 17

The experimental protocol used is the same as that described forcompound 1, withN-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-ureareplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, awhite powder is obtained with a yield of 45%. Melting point: 236-237° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.42 (wide s, 1H, NH⁺); 9.77 (wide s, 1H,NH⁺); 8.92 (wide s, 1H, NH⁺); 8.54 (s, 1H, NH-Ph); 8.11 (m, 2H,thiophene); 7.41 (m, 5H, Ph-N, thiophene); 7.19 (s, 2H, Ph); 6.70 (m,1H, NH—CH₂); 6.60 (s, 1H, OH); 4.35 (d, 2H, CH₂, J=5.5 Hz); 1.34 (s,18H, 2× tBu).

IR: ν_(OH): 3624 cm⁻¹; ν_(C═O) (urea): 1644 cm⁻¹; ν_(C═N) (amidine):1569 cm⁻¹.

Example 18

N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamideHydrochloride: 18

18.1)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide

1.78 g (6.4 mmoles) of 3,5-di-tert-butyl-4-hydroxycinnamic acid, 0.99 g(6.4 mmoles) of 4-amino-2-nitrophenol, previously diluted in 10 ml ofDMF, 0.86 g (6.4 mmoles) of hydroxybenzotriazol and 1.32 g (6.4 mmoles)of dicyclohexylcarbodiimide are introduced into a 50 ml flask containing10 ml of THF. The reaction medium is agitated for 15 hours at ambienttemperature, the precipitate which appears is filtered and rinsed withethyl acetate. After concentration of the solution under reducedpressure, the residue is diluted in 20 ml of ethyl acetate and theinsoluble part is filtered again. The filtrate is washed with 20 ml of asaturated solution of sodium carbonate followed by 20 ml of water and 20ml of a saturated solution of sodium chloride. After drying over sodiumsulphate, the organic solution is filtered and concentrated to drynessunder reduced pressure. The residue is purified on a silica column(eluant: heptane/ethyl acetate: 8/2). The pure fractions are collectedand concentrated under vacuum to produce 1.95 g (47%) of the expectedcompound in the form of a yellow-orange powder. Melting point: 231-232°C.

NMR ¹H (100 MHz, CDCl₃, δ): 10.45 (s, 1H, NH); 8.45 (d, 1H, Ph-NO₂,J=1.7 Hz); 7.98 (dd, 1H, Ph-NO₂, J=1.7 Hz and J=6.8 Hz); 7.78 (d, 1H,—CH═CH—, J=10.5 Hz); 7.75 (s, 1 H, OH); 7.40 (s, 2H, Ph-OH); 7.20 (d,1H, Ph-NO₂); 6.48 (d, 1H, —CH═CH—); 5.51 (s, 1H, OH); 1.50 (s, 18H,2×tBu).

18.2)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide

In a 100 ml flask equipped with a refrigerant, 0.9 g (2.18 mmoles) of3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamideis dissolved in 20 ml of ethyl acetate, 2.46 g (10.9 mmoles) of tinchloride (dihydrate) is added and the mixture is heated at 70° C. forthree hours. After returning to ambient temperature, the reaction mediumis poured onto an agitated solution of sodium bicarbonate (0.1 M), aprecipitate forms, which is eliminated by filtration on celite. Thefiltrate is decanted and the aqueous phase is extracted with 20 ml ofethyl acetate. The organic phases are collected together and washed with20 ml of water followed by 20 ml of a saturated solution of sodiumchloride. After drying over sodium sulphate and filtration, the organicsolution is concentrated to dryness, under partial vacuum. Theevaporation residue is suspended in a heptane/ethyl acetate mixture(1/1) and filtered to produce a yellowish powder with a yield of 53%.The product is used as it is in the following stage.

18.3)N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamideHydrochloride: 18

The experimental protocol used is the same as that described forcompound 1, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:35/65). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 10 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. 0.35 g (62%) of a yellow powder is obtained. Melting point:199-200° C.

NMR ¹H (400 MHz, DMSO, δ): 11.11 (s, 1H, NH⁺); 10.29 (s, 1H, NH⁺); 10.17(s, 1H, NH⁺); 9.71 (s, 1H, CONH); 8.61 (wide s, 1H, OH); 8.14 (m, 2H,thiophene); 7.79 (s, 1H, Ph-N); 7.53 (m, 1H, Ph-N); 7.48 (d, 1H,—CH═CH—, J=14.7 Hz); 7.37 (m, 4H, Ph-tBu+OH+Ph-N); 7.05 (m, 1H,thiophene); 6.68 (d, 1H, —CH═CH—); 1.41 (s, 18H, 2×tBu).

IR: ν_(OH): 3624 cm⁻¹, 3415 cm⁻¹; ν_(C═O) (amide): 1656 cm⁻¹; ν_(C═C):1616 cm⁻¹; ν_(C═N) (amidine): 1587 cm⁻¹.

Example 19

N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamideHydrochloride: 19

19.1)3-[(3,5-bis-(1,1dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide

The experimental protocol used is the same as that described forintermediate 18.1, with 2-amino-4-nitrophenol replacing the4-amino-2-nitrophenol. A light yellow powder is obtained with a yield of25%. Melting point: 256-257° C.

NMR ¹H (400 MHz, DMSO, δ): 11.79 (wide s, 1H, OH); 9.59 (s, 1H, NH);9.21 (wide s, 1H, Ph-NO₂); 7.90 (badly resolved dd, 1H, Ph-NO₂, J=8.1Hz); 7.52 (d, 1H, —CH═CH—, J=15.5 Hz); 7.47 (s, 1H, OH); 7.42 (s, 2H,Ph-OH); 7.15 (d, 1H, —CH═CH—); 7.04 (d, 1H, Ph-NO₂); 1.42 (s, 18H,2×tBu).

19.2)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamide

The experimental protocol used is the same as that described forintermediate 18.2, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamidereplacing the3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide.A yellow powder is obtained with a yield of 74%. The product is usedwithout additional purification in the following stage.

19.3)N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamideHydrochloride: 19

The experimental protocol used is the same as that described forcompound 1, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, ayellow powder is obtained with a yield of 54%. Melting point: 256-257°C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.32 (s, 1H, NH⁺); 10.67 (s, 1H, NH⁺);9.69 (s, 1H, NH⁺); 9.55 (s, 1H, CONH); 8.70 (wide s, 1H, OH); 8.19 (m,2H, thiophene); 7.48 (d, 1H, —CH═CH—, J=15.5 Hz); 7.40 (s, 2H, Ph-tBu);7.37 (m, 2H, Ph-N); 7.34 (s, 1H, OH); 7.13 (d, 1H, —CH═CH—); 7.10 (m,1H, Ph-N); 6.99 (m, 1H, thiophene); 1.41 (s, 18H, 2×tBu).

IR: ν_(OH): 3623 cm⁻¹, 3410 cm⁻¹; ν_(C═O) (amide): 1652 cm⁻¹; ν_(C═C):1616 cm⁻¹; ν_(C═N) (amidine): 1587 cm⁻¹.

Example 20

N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 20

20.1) 5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol

The experimental protocol is the same as that described for intermediate8.1, with 1-(4-nitrophenyl)piperazine replacing the4-nitrophenetylamine. A yellow powder still containing traces ofimpurities is obtained with a yield of 43%.

NMR ¹H (100 MHz, DMSO, δ): 9.17 (wide s, 2H, 2× —OH); 8.55 (wide s, 1H,—OH); 7.57 (m, 4H, Ph-NO₂); 6.40 (s, 2H, Ph-OH); 3.59 (badly resolved m,8 H, piperazine).

20.2) 5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol

The experimental protocol used is the same as that described forintermediate 2.2, with5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A beige powder is obtained with a yield of 61%. This is used directly inthe following stage without additional purification.

NMR ¹H (100 MHz, DMSO, δ): 9.12 (wide s, 2H, 2× —OH); 8.55 (wide s, 1H,—OH); 6.61 (m, 4H, Ph-NH₂); 6.34 (s, 2H, Ph-OH); 3.59 (m, 4H,piperazine); 2.89 (m, 4H, piperazine).

20.3)N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 20

The experimental protocol used is the same as that described forcompound 1, with5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftertreatment with a molar solution of HCl in anhydrous diethyl ether, abrown powder is obtained with a yield of 25%. Melting point: 198-205° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.38 (s, 1H, NH⁺); 9.75 (s, 1H, NH⁺);9.00 (wide s, 1H, OH); 8.75 (s, 1H, NH⁺); 8.15 (m, 2H, thiophene); 7.39(m, 1H, thiophene); 7.22 (m, 4H, Ph-N); 6.40 (s, 2H, Ph); 5.11 (wide s,2H, 2×OH); 3.65 (m, 4H, piperazine); 3.29 (m, 4H, piperazine).

IR: ν_(OH): 3399 cm⁻¹; ν_(C═O) (amide): 1696 cm⁻¹; ν_(C═N) (amidine):1588 cm⁻¹.

Example 21

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-ureaHydrochloride: 21

21.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)-carbonylamino]-urea

0.22 g (0.73 mmole) of triphosgene at 20° C. is dissolved in a 50 mlthree-necked flask equipped with an addition funnel, under an argonatmosphere. Over one hour, a solution of 0.44 g (2 mmoles) of4-amino-2,6-bis-(1,1-dimethylethyl)-phenol (intermediate 17.1) and 0.38ml (2.2 mmoles) of diisopropylethylamine in 7 ml of anhydrousdichloromethane is added dropwise to this mixture. Five minutes afterthe end of this addition, a solution of 0.36 g (2 mmoles) of4-nitrobenzoyl-hydrazide and 0.38 ml (2.2 mmoles) ofdiisopropylethylamine in 4 ml of anhydrous DMF is added in a singleportion. After agitation for four hours at 20° C., the reaction mediumis concentrated to dryness under reduced pressure. The evaporationresidue is diluted in 40 ml of ethyl acetate and the organic solution iswashed successively with 3 times 20 ml of water and 20 ml of a saturatedsolution of sodium chloride. After drying over sodium sulphate, theorganic solution is filtered and the filtrate concentrated to drynessunder reduced pressure. The residue obtained is suspended in heptane,agitated and filtered to produce a yellow powder with a yield of 86%.Melting point: 163-164° C.

NMR ¹H (100 MHz, DMSO d6, δ): 10.65 (wide s, 1H, NH amide); 8.72 (s, 1H,NH-Ph); 8.38 (m, 4H, Ph-NO₂); 8.20 (s, 1H, CO—NH—NH); 7.36 (s, 2H,Ph-OH); 6.78 (s, 1H, OH); 1.50 (s, 18H, 2×tBu).

21.2)N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea

In a 250 ml Parr flask, 0.72 g (1.68 mmoles) ofN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)carbonylamino]-ureais dissolved in 30 ml of absolute ethanol in the presence of 10% Pd/C.The mixture is agitated under 20 PSI of hydrogen, at 30° C., for twohours. After filtration on celite, the filtrate is concentrated undervacuum. The evaporation residue is suspended in diethyl ether (20 ml),agitated and filtered to produce a pale yellow powder with a yield of75%. Melting point: 245-246° C.

NMR ¹H (100 MHz, DMSO d6, δ): 9.84 (wide s, 1H, NH amide); 8.56 (s, 1H,NH-Ph); 7.85 (m, 2H, Ph-NH₂); 7.74 (s, 1H, CO—NH—NH); 7.38 (s, 2H,Ph-OH); 6.78 (s, 1H, OH); 6.60 (m, 2H, Ph-NH₂); 5.80 (wide s, 2H, NH₂);1.50 (s, 18H, 2×tBu).

21.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-ureaHydrochloride: 21

The experimental protocol used is the same as that described forcompound 1, with N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxy phenyl]-ureareplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:1/1). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 15 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. 0.40 g (58%) of a yellow powder is obtained. Melting point:254-255° C.

NMR ¹H (400 MHz, DMSO, δ): 11.68 (wide s, 1H, NH⁺); 10.32 (s, 1H, NHamide); 9.94 (wide s, 1H, NH⁺); 9.13 (wide s, 1H, NH⁺); 8.68 (s, 1H,NH-CO); 8.18 (m, 2H, thiophene); 8.07 (m, 3H, CO—NH—NH+Ph-NH); 7.58 (m,2H, Ph-NH); 7.39 (m, 1H, thiophene); 7.22 (s, 2H, Ph-OH); 6.60 (s, 1H,OH); 1.36 (s, 18H, 2×tBu).

IR: ν_(OH): 3627 cm⁻¹; ν_(C═O) (amide), ν_(C═O) (urea): 1654 cm⁻¹, 1602cm⁻¹; ν_(C═N) (amidine): 1559 cm⁻¹.

Example 22

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thioureaHydrochloride: 22

22.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-thiourea

Compound 22.1 is obtained by the action of Lawesson's reagent onintermediate 17.4 according to an experimental protocol described in theliterature (J. Med. Chem. (1995), 38 (18), 3558-3565). A light yellowpowder is obtained with a yield of 80%. Melting point: 218-220° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph-NO₂); 7.70 (s, 1H, NH-Ph);7.05 (s, 2H, Ph-OH); 6.21 (m, 1H, NH-CH₂); 5.40 (s, 1H, OH); 5.00 (d,2H, CH₂, J=6.5 Hz); 1.41 (s, 18H, 2×tBu).

22.2)N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea

The experimental protocol used is the same as that described forintermediate 18.2, with intermediate 22.1 replacing the3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide.A beige powder is obtained with a yield of 70%. Melting point: 167-169°C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.48 (wide s, 1H, NH-Ph); 6.95 (s, 2H,Ph-OH); 6.81 (m, 4H, Ph-NH₂); 5.98 (m, 1H, NH—CH₂); 5.28 (s, 1H, OH);4.69 (d, 2H, CH₂, J=5.5 Hz); 3.62 (wide s, 2H, NH₂); 1.40 (s, 18H,2×tBu).

22.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thioureaHydrochloride: 22

The experimental protocol used is the same as that described forintermediate 17.6, with intermediate 22.2 replacing theN-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea.A pale yellow powder is obtained with a yield of 15%. Melting point:203-205° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.52 (wide s, 1H, NH⁺); 9.86 (wide s, 1H,NH⁺); 8.98 (wide s, 1H, NH⁺); 8.39 (s, 1H, NH-Ph); 8.16 (m, 2H,thiophene); 7.46 (m, 6H, Ph-N, thiophene, NH-CH₂); 7.18 (s, 2H, Ph);6.92 (s, 1H, OH); 4.80 (wide s, 2H, CH₂); 1.35 (s, 18H, 2×tBu).

IR: ν_(OH): 3630 cm⁻¹; ν_(C═O) (urea): 1649 cm⁻¹; ν_(C═N) (amidine):1600 cm⁻¹.

Example 23

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-urea Hydrochloride: 23

23.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[2-(4-nitrophenyl)ethyl]-urea

The experimental protocol used is the same as that described forintermediate 21.1, with 4-nitrophenetylamine replacing the4-nitrobenzoyl-hydrazide. A beige powder is obtained with a yield of80%. Melting point: 185-187° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.75 (m, 4H, Ph-NO₂); 7.00 (s, 2H, Ph-OH);6.05 (s, 1H, OH); 5.18 (s, 1H, NH); 4.68 (m, 1H, NH—CH₂); 3.50 (m, 2H,NH-CH ₂); 2.92 (m, 2H, CH₂); 1.40 (s, 18H, 2×tBu).

23.2)N-[2-(4-aminophenyl)ethyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea

The experimental protocol used is the same as that described forintermediate 21.2, with intermediate 23.1 replacing theN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)-carbonylamino]-urea.A white powder is obtained with a yield of 56%. Melting point: 192-194°C.

NMR ¹H (100 MHz, DMSO d6, δ): 8.25 (wide s, 1H, Ph-NH—CO); 7.22 (s, 2H,Ph-OH); 6.79 (m, 4H, Ph-NH₂); 6.65 (s, 1H, OH); 5.92 (m, 1H, NH-CH₂);4.98 (wide s, 2H, —NH₂); 3.31 (m, 2H, NH—CH ₂); 2.65 (m, 2H, CH₂); 1.48(s, 18H, 2×tBu).

23.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-ureaHydrochloride: 23

The experimental protocol used is the same as that described forcompound 1, with intermediate 23.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:1/1). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 15 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. Finally, 0.25 g (24%) of a pale yellow powder is obtained.Melting point: 207-210° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.48 (wide s, 1H, NH⁺); 9.83 (wide s, 1H,NH⁺); 8.95 (wide s, 1H, NH⁺); 8.50 (s, 1H, NH—CO); 8.18 (m, 2H,thiophene); 7.38 (m, 5H, Ph-NH+thiophene); 7.18 (s, 2H, Ph-OH); 6.55 (s,1H, OH); 6.21 (m, 1H, CO—NH—CH₂); 3.35 (m, 2H, NH—CH ₂); 2.78 (m, 2H,CH₂); 1.36 (s, 18H, 2×tBu).

IR: ν_(OH): 3631 cm⁻¹; ν_(C═O) (urea): 1654 cm⁻¹, 1600 cm⁻¹; ν_(C═N)(amidine): 1560 cm⁻¹.

Example 24

N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamideHydrochloride: 24

24.1)1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-nitrophenyl)piperazine

The experimental protocol is identical to that described forintermediate 13.1, with(±)-3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxyliqueacid (prepared according to CHIMIA (1991), 45 (4), 121-3) replacing the(±)-Trolox®. A yellow powder is obtained.

NMR ¹H (100 MHz, CDCl₃, δ): 7.45 (m, 4H, Ph); 3.60 (s, 3H, CH₃O); 3.40(m, 4H, piperazine); 3.00 (m, 4H, piperazine); 2.50-1.60 (m, 16H,Trolox®).

24.2)1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-aminophenyl)piperazine

The experimental protocol is identical to that described forintermediate 13.2, with intermediate 24.1 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.An oil is obtained which is used directly in the following stage.

NMR ¹H (100 MHz, CDCl₃, δ): 6.70 (m, 4H, Ph); 3.90 (wide d, 4H,piperazine); 3.60 (s, 3H, CH₃O); 3.45 (wide s, 2H, NH₂); 2.90 (m, 4H,piperazine); 2.60-1.60 (m, 18H, Trolox®).

24.3)N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamideHydrochloride: 24

The experimental protocol is the same as that described for compound 13,with intermediate 24.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol. A pale yellow powder is obtained. Melting point:190-195° C.

NMR ¹H (400 MHz, DMSO, δ): 11.35 (wide s, 1H, NH⁺); 9.70 (wide s, 1H,NH⁺); 8.70 (wide s, 1H, NH⁺); 8.15 (wide s, 2H, thiophene); 7.35 (wides, 1H, thiophene); 7.17 (m, 4H, Ph); 3.90 (wide d, 4H, piperazine); 3.50(s, 3H, CH₃O); 3.15 (m, 4H, piperazine); 2.55-1.55 (m, 16H, Trolox®).

IR: ν_(C═O) (amide): 1642 cm⁻¹; ν_(C═N) (amidine): 1618 cm⁻¹.

Example 25

N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamideHydrochloride: 25

25.1) hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine

3.37 g (24.4 mmoles) of potassium carbonate and 1.89 g (13.4 mmoles) of4-nitrofluorobenzene are added to a solution of 2.44 g (12.2 mmoles) of(1,1-dimethyl)ethyl hexahydro-1H-1,4-diazepine-1-carboxylate in 50 ml ofDMF. The reaction medium is heated at 100° C. for 16 hours. Aftercooling down, 25 ml of ethyl acetate and 50 ml of water are added. Theorganic solution is decanted and the aqueous phase extracted with 3times 50 ml of ethyl acetate. The organic phases are collected togetherand washed with 50 ml of brine, dried over sodium sulphate, filtered andconcentrated under vacuum. 3.7g of a bright yellow solid is obtainedwith a yield of 95%. This solid is then dissolved in 100 ml of a mixtureof solvents (dichloromethane/ethyl acetate 1:1) to which 20 ml of a 6Naqueous solution of hydrochloric acid is added dropwise at 0° C. Aftervigorous agitation at 20° C. for 1 hour, the reaction medium isdecanted. The aqueous phase is basified to pH=11 with 4N soda andextracted with 3 times 50 ml of dichloromethane. The organic phases arecollected, washed with 50 ml of water followed by 50 ml of brine, driedover sodium sulphate and finally filtered and concentrated under vacuum.1.78 g of a bright yellow powder is obtained with a yield of 66%. Theproduct is used directly in the following stage without additionalpurification.

NMR ¹H (100 MHz, CDCl₃, δ): 8.10 (m, 2H, Ph); 6.65 (m, 2H, Ph); 3.70 (q,4H, CH₂N, J=5.2 Hz); 3.10 (t, 2H, CH₂N); 2.85 (t, 2H, CH₂N); 1.95 (q,2H, C—CH₂—C); 1.65 (wide s, 1H NH).

25.2)1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine

In a 50 ml flask, 0.71 g (4.4 mmoles) of 1,1′-carbonyldiimidazole isadded to a solution of 1.07 g (4.3 mmoles) of (±)-Trolox® in 8 ml ofanhydrous THF. After agitation for one hour at 20° C., a solution of0.95 g (4.3 mmoles) of intermediate 25.1 in 4 ml of DMF is addeddropwise. The reaction medium is agitated for 16 hours at 20° C. Afterevaporation of the solvents under vacuum, the residue is taken up in 30ml of a mixture of solvents (dichloromethane/water 1:2). Afterdecanting, the organic phase is washed with 2 times 20 ml of water,dried over sodium sulphate and concentrated under vacuum. A pale yellowpowder is obtained with a gross yield of 97%. The product is useddirectly in the following stage without additional purification.

NMR ¹H (100 MHz, CDCl₃, δ): 8.10 (m, 2H, Ph); 6.60 (m, 2H, Ph); 4.40(wide s, 1H, OH); 3.50 (m, 8H, CH₂N); 2.50-1.50 (m, 18H, Trolox®+CH₂).

25.3)1-(4-aminophenyl)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepine

The experimental protocol used is the same as that described forintermediate 13.2, with intermediate 25.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.The product of the reaction is purified on a silica gel column (eluant:ethyl acetate/petroleum ether 3:2). An oil is obtained with a yield of57%.

25.4)N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamideHydrochloride

A mixture of 0.52 g (1.22 mmole) of intermediate 25.3 and 0.35 g (1.22mmole) of S-methyl-2-thiophene thiocarboximide hydriodide in 4 ml ofisopropanol is heated at 50° C. for 40 hours. The reaction medium isthen filtered and the solid obtained is taken up in 4 ml of a saturatedaqueous solution of sodium carbonate and 4 ml of ethyl acetate. Themixture is heated at 50° C. for 30 minutes, then decanted. The organicphase is washed twice with 10 ml of water followed by 10 ml of brine.The organic phases are collected, dried over sodium sulphate, filteredand concentrated under reduced pressure. The solid obtained is purifiedon a silica gel column (eluant: ethyl acetate/petroleum ether 5:1). 0.5g of product is obtained with a yield of 77%. 0.15 g (0.29 mmole) ofthis product is then dissolved in 2 ml of acetone. 0.84 ml (0.84 mmole)of a 1N hydrochloric acid solution in anhydrous ethyl ether is addeddropwise. The whole is agitated at ambient temperature for 30 minutes. Ayellow precipitate forms which is filtered. The precipitate istriturated and washed successively with 3 times 5 ml of ethyl ether and5 ml of acetone. The dark yellow powder is dried under vacuum at 70° C.for 48 hours. The yield obtained is 80%. Melting point: 180-185° C.

NMR ¹H (400MHz, DMSO, δ): 11.15 (wide s, 1H, NH⁺); 9.60 (wide s, 1H,NH⁺); 8.55 (wide s, 1H, NH⁺); 8.10 (wide s, 2H, thiophene); 7.35 (wides, 1H, thiophene); 7.02 (m, 4H, Ph); 4.80 (wide s, 1H, OH); 3.70 (m, 8H,CH₂N); 2.50-1.40 (m, 18H, Trolox®+CH₂).

IR: ν_(OH): 3412 cm⁻¹; ν_(C═O) (amide): 1613 cm⁻¹; ν_(C═N) (amidine):1613 cm⁻¹.

Example 26

(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 26

26.1)(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-⁶-ol

The experimental protocol used is the same as that described forcompound 13.1, with (R)-Trolox® replacing the (±)Trolox®. A brightyellow powder is obtained with a yield of 98%. Melting point: 102-105°C.

26.2)(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol

The experimental protocol used is the same as that described forintermediate 2.2, with intermediate 26.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A pink powder is obtained with a yield of 75%. The product is used as itis in the following stage. Melting point: 103-105° C.

26.3)(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl }-2-thiophenecarboximidamide Hydrochloride: 26

The experimental protocol used is the same as that described forcompound 13, with intermediate 26.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.The product is obtained in the form of a pale yellow powder whichhydrates in air. Melting point: 195-197° C.

The NMR and IR analyses are identical to compound 13.

[α]_(D) ²⁰=−43.5° (c=0.11; DMSO)

Example 27

(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideDihydrochloride: 27

27.1)(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol

The experimental protocol used is the same as that described forcompound 13.1, with (S)-Trolox® replacing the (±)Trolox®. A yellowpowder is obtained with a yield of 73%. Melting point: 110-111° C.

27.2)(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol

The experimental protocol used is the same as that described forintermediate 2.2, with intermediate 27.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.After purification on a silica gel column (heptane/ethyl acetate: 2/8),collection and evaporation under vacuum of the pure fractions, a beigepowder is obtained with a yield of 54%. Melting point: 109-111° C.

27.3)(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideDihydrochloride: 27

The experimental protocol used is the same as that described forcompound 13, with intermediate 27.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol. The product is obtained in the form of a paleyellow powder which hydrates in air. Melting point: 210.6-211.8° C.

The NMR and IR analyses are identical to compound 13.

[α]²⁰ _(D)=+76.2° (c=0.17; DMSO)

Alternatively, compound 27 can be prepared according to the followingprotocol:

27.4) Methyl 2-thiophene Carboximidate

10.91 g (0.1 mole) of 2-thiophene carbonitrile, 100 ml of anhydrousethyl ether and 4.5 ml (0.11 mole) of methanol are introduced into a 250ml erlen meyer flask purged with argon. The solution is cooled down to0° C. using an ice bath and saturated with a stream of anhydrous gaseousHCl for 45 minutes. The reaction medium is agitated for an additionalhour at 0° C. and overnight at 20° C. The precipitate formed is filteredout, washed with ethyl ether and dried. The hydrochloride obtained ispartitioned into a mixture of 100 ml of water and 150 ml of ethyl ether.The medium is neutralized by adding 8.4 g (0.1 mole) of dry NaHCO₃.After decanting and separation, the organic phase is washed successivelywith 2×30 ml of water and 30 ml of brine. After drying over magnesiumsulphate, the organic solution is filtered and concentrated undervacuum. A colourless oil is obtained with a yield of 66%.

NMR ¹H (400 MHz, CDCl₃, δ): 7.58 (wide s, 1H, ═N—H); 7.42 (m, 1H,thiophene); 7.37 (m, 1H, thiophene); 7.01 (m, 1H, thiophene); 3.86 (s,3H, OCH₃).

IR: ν_(C═N) (carboximidate): 1630 cm⁻¹.

27.5)(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideDihydrochloride: 27

In a 150 ml erlen meyer flask, under a stream of argon, 8.2g (20 mmoles)of(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol (obtained as intermediate 13.2 but from(S)-Trolox®), is dissolved in 60 ml of methanol and 4.2 g (30 mmoles) ofmethyl 2-thiophene carboximidate is added. The reaction medium is heatedfor 18 hours under reflux. The methanol is evaporated under vacuum andthe oily brown residue is purified on a silica gel column (eluant:dichloromethane/ethanol: 95/5). The pure fractions are collected andconcentrated under vacuum to produce a brown oil with a yield of 68%.This oil is taken up in 22 ml of an ethanolic solution of HCl (1.3N) anddiluted with 180 ml of anhydrous acetone. The reaction medium isagitated for 1 hour at 0° C. The precipitate formed is filtered andwashed successively with acetone and ethyl ether. After drying, thedihydrochloride is obtained in the form of a pale yellow powder with ayield of 53%.

Example 28

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamideHydrochloride: 28

28.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)ethyl]-benzamide

The experimental protocol used is the same as that described forintermediate 5.1, with 3-nitrophenetylamine (J. Med. Chem. (1968), 11(1), 21-26) replacing the 4-nitrophenetylamine. A white powder isobtained with a yield of 50%. Melting point: 195-197° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.86 (m, 4H, Ph-NO₂); 7.50 (s, 2H, Ph); 6.10(m, 1H, NHCO); 5.54 (s, 1H, OH); 3.75 (m, 2H, CH ₂—NHCO); 3.08 (m, 2H,CH ₂-Ph-NO₂); 1.42 (s, 18H, 2×tBu).

28.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-aminophenyl)ethyl]-benzamide

The experimental protocol used is the same as that described forintermediate 5.2, with intermediate 28.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide.A white powder is obtained (yield of 40%) which is sufficiently pure tobe used directly in the following stage.

28.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamideHydrochloride: 28

The experimental protocol used is the same as that described forintermediate 1.3, with intermediate 28.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Apale yellow powder is obtained with a yield of 35%. Melting point:205-207° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.59 (wide s, 1H, NH⁺); 9.89 (s, 1H,NH⁺); 8.95 (s, 1H, NH⁺); 8.46 (s, 1H, CONH); 8.17 (m, 2H, thiophene);7.54 (s, 2H, Ph-OH); 7.39 (m, 6H, thiophene, Ph-NH, OH); 3.51 (m, 2H, CH₂—NHCO); 2.89 (m, 2H, CH ₂-Ph-NH); 1.38 (s, 18H, 2×tBu).

IR: ν_(OH): 3624 cm⁻¹; ν_(C═O) (amide): 1631 cm⁻¹; ν_(C═N) (amidine):1577 cm⁻¹.

Example 29

N-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinyl)phenyl}-2-thiophene-carboximidamideHydrochloride: 29

The experimental protocol used is the same as that described for thecompound 9, with 3,5-di-tert-butyl-4-hydroxyphenylacetic acid replacingthe 3,5-di-tert-butyl-4-hydroxybenzoic acid in the first stage ofsynthesis. Yellow powder. Melting point: 176-180° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.30 (wide s, 1H, NH⁺); 9.70 (wide s, 1H,NH⁺); 8.65 (wide s, 1H, NH⁺); 8.10 (wide s, 2H, thiophene); 7.35 (wides, 1H, thiophene); 7.12 (m, 4H, Ph-N); 6.95 (s, 2H, Ph-OH); 6.80 (wides, 1H, OH); 3.60 (wide s, 6H, piperazine, CH₂CO); 3.10 (m, 4H,piperazine); 1.35 (s, 18H, 2× tBu).

IR: ν_(OH): 3620 cm⁻¹: ν_(C═O) (ester): 1638 cm−1; ν_(C═N) (amidine):1612 cm⁻¹.

Example 30

2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate Hydrochloride: 30

30.1) 2-(4-nitrophenyl)ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate

In a 250 ml flask containing 80 ml of THF, under an argon atmosphere,2.45 g (9.8 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.8 g(10.8 mmoles) of 4-nitrobenzene-ethanol and 2.2 g (10.8 mmoles) ofdicyclohexylcarbodiimide are introduced successively, under agitation.The reaction medium is agitated for 15 hours at 20° C. and theprecipitate which appears is filtered out. The filtrate is washed with2×30 ml of a saturated NaCl solution, the organic phase is dried overmagnesium sulphate, filtered and concentrated under vacuum. The residueis then crystallized using di-isopropyl ether. The solid is recovered byfiltration and 2.4 g (62%) of white crystals are obtained after drying.Melting point: 123.5-124.5° C.

NMR 1H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph-NO₂); 7.80 (s, 2H, Ph-OH);5.70 (s, 1H, OH); 4.50 (m, 2H, O—CH₂); 3.20 (m, 2H, CH₂); 1.40 (s, 18H,2× tBu).

30.2) 2-(4-aminophenyl)ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate

The experimental protocol is the same as that described for intermediate2.2, with intermediate 30.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)-methyl]-benzamide.A white powder is obtained with a yield of 50%. Melting point: 135-136°C.

NMR 1H (400 MHz, DMSO d6, δ): 7.75 (s, 2H, Ph-OH); 6.70 (m, 4H, Ph-N);4.90 (wide s, 1H, OH); 4.25 (m, 2H, O—CH₂); 3.30 (wide s, 2H, NH₂); 2.80(m, 2H, CH₂); 1.40 (s, 18H, 2×tBu).

30.3) 2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate Hydrochloride: 30

The experimental protocol is the same as that described for intermediate1.3, with intermediate 30.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Awhite solid is obtained with a yield of 26%. Melting point: 145-150° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.80 (wide s, 1H,NH⁺); 8.90 (wide s, 1H, NH⁺); 8.20 (wide s, 2H, thiophene); 7.85 (s, 1H,OH); 7.75 (s, 2H, Ph-OH); 7.47 (m, 5H, Ph-N, thiophene); 4.41 (m, 2H,O—CH₂); 3.08 (m, 2H, CH₂);1.40 (s, 18H, 2×tBu).

IR: ν_(C═O) (ester): 1700 cm⁻¹; ν_(C═N) (amidine): 1592 cm⁻¹.

Example 31

2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate Hydrochloride: 31

The experimental protocol used is the same as that described for thecompound 30, with 3-nitrobenzene-ethanol replacing the4-nitrobenzene-ethanol in the first stage of synthesis. Pale yellowpowder. Melting point: 145-148° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.82 (wide s, 1H,NH⁺); 8.99 (wide s, 1H, NH⁺); 8.15 (m, 2H, thiophene); 7.81 (s, 1H, OH);7.75 (s, 2H, Ph-OH); 7.41 (m, 5H, Ph-N, thiophene); 4.41 (m, 2H, O—CH₂);3.08 (m, 2H, CH₂); 1.38 (s, 18H, 2×tBu).

IR: ν_(OH): 3620 cm⁻¹; ν_(C═O) (ester): 1707 cm⁻¹; ν_(C═N) (amidine):1654 cm⁻¹.

Example 32

2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate Hydrochloride: 32

The experimental protocol used is the same as that described forcompound 30, with 2-nitrobenzene-ethanol replacing the4-nitrobenzene-ethanol in the first stage of synthesis. Beige powder.Melting point: 139-145° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.80 (wide s, 1H,NH⁺); 8.65 (wide s, 1H, NH⁺); 8.15 (m, 2H, thiophene); 7.80 (s, 1H, OH);7.70 (s, 2H, Ph-OH); 7.60 (m, 1H, Ph); 7.45 (m, 3H, Ph); 7.35 (s, 1H,thiophene); 4.40 (m, 2H, O—CH₂); 3.00 (m, 2H, CH₂); 1.35 (s, 18H,2×tBu).

IR: ν_(C═O) (ester): 1728 cm⁻¹; ν_(C═N) (amidine): 1649 cm⁻¹.

Example 33

N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide Hydroiodide(33)

33.1 1-(4-nitrophenyl)-1H-imidazole

9 g (64.5 mmoles) of potassium carbonate and 5 g (3.75 ml; 35.2 mmol) of1-fluoro-4-nitrobenzene are added to a solution of 2 g of imidazole(29.4 mmol) in 14 ml of DMF. The reaction mixture is agitated for 1.5hours at 110° C. Ethyl acetate (50 ml) is added to the medium which iswashed 3 times with 50 ml of water. The organic phases are dried overmagnesium sulphate and concentrated under vacuum. 4.4 g of product arethus obtained (yield=80%) in the form of a clear oil and used withoutfurther purification in the following stages.

NMR ¹H (CDCl₃, 100 MHz, δ): 6.92 (t, 1H, Arom. H imidazole), 7.16 (s,1H, Arom. H imidazole), 7.24-7.32-8.18-8.27 (4s, 4H, Arom. H), 7.59 (s,1H, Arom. H imidazole).

33.2 1-(4-aminophenyl)-1H-imidazole

1-(4-nitrophenyl)-1H-imidazole (4.4 g; 23.5 mmoles) is put in solutionin anhydrous methanol (140 ml) and palladium on carbon (0.44 g) is addedto the medium. The reaction medium is placed under hydrogen for 4 hours.The catalyst is filtered off and the solvent is evapored to dryness. Theexpected product is obtained in a virtually pure state with a yield of89% (3.3 g).

NMR ¹H (CDCl₃, 100 MHz, δ): 6.61-6.69-6.95-7.05 (4s, 4H, Arom. H), 6.88(t, 1H, Arom. H imidazole), 7.07 (s, 1H, Arom. H imidazole), 7.52 (s,1H, Arom. H imidazole).

33.3 N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamideHydroiodide (33)

1-(4-aminophenyl)-1H-imidazole (0.3 g; 1.7 mmoles) andS-methyl-2-thiophenethiocarboximide hydroiodide (0.5 g; 1.75 mmoles) areput into solution in 1 ml isopropanol and 1 ml of DMF and the reactionmixture is agitated for 18 hours at 25° C. The precipitate formed isfiltered and washed with 15 ml of dichloromethane and 15 ml of ethanol.The expected product is thus obtained (0.48 g; 73%) in salified form(hydroiodide). Melting point: 252-253° C. (decomposition).

NMR ¹H (DMSO, 400 MHz, δ): 7.24 (s, 1H, arom. H). 7.38 (t, 1H, arom. H).7.55-7.57-7.85-7.87 (4s, 4H, arom. H), 7.89 (s, 1H, arom. H), 8.10 (m.2H, arom. H), 8.50 (s, 1H, arom. H).

IR: ν_(C═N) (amidine): 1585 cm⁻¹.

Example 34

N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide (34)

34.1 1-bromomethyl-4-nitrobenzene

4-nitrobenzyl alcohol (6 g, 39 mmoles) is put into solution indichloromethane (100 ml) and carbon tetrabromide (14.9 g, 45 mmoles) isadded. Triphenylphosphine (11.8 g, 45 mmoles) is added in portions tothe medium at 0° C. Then the mixture is agitated for 2 hours at ambienttemperature. The solvent is evaporated off and the product obtained ispurified on silica gel in an ethyl acetate/heptane mixture (1/2). It isobtained in the form of white needle-shaped crystals (7.2 g; 85%).Melting point: 97-98° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 4.53 (s, 2H, CH₂). 7.53-7.61-8.18-8.27 (4 H,Arom. H).

34.2 3-(4-nitrobenzyl)-thiazolidine

A mixture of thiazolidine (0.9 g, 10 mmoles) and potassium carbonate(2.5 g, 18 mmoles) in acetonitrile (10 ml) is heated to 70° C.1-bromomethyl-4-nitrobenzene (2 g, 9.2 mmoles) in solution inacetonitrile (25 ml) is added dropwise and the reaction is maintainedunder reflux for 2 hours.

The precipitate formed is filtered, the mother liquors are evaporatedand the residue is taken up in 50 ml of dichloromethane and washed 3times with 50 ml of water. The organic phases are dried, evaporated andpurified over silica gel in an ethyl acetate/heptane mixture (1/2). Theexpected product is obtained in the form of a colourless oil (1.5 g,72%).

NMR 1H (CDCl₃, 100 MHz, 6): 3.05 (m, 4H, 2CH₂), 3.68 (s, 2H, CH₂—S),4.04 (s, 2H, CH₂), 7.53-7.62-8.17-8.26 (4s, 4H, Arom. H).

34.3 3-(4-aminobenzyl)-thiazolidine

3-(4-nitrobenzyl)-thiazolidine (1.1 g, 5 mmoles) is put into solution in10 ml concentrated hydrochloric acid at 0° C. Dihydrated tin chloride(7.7 g, 34 mmoles) is added in portions, the mixture is heated for 2hours under reflux and the acid is evaporated off under reducedpressure. The residue is then taken up in 20 ml of water and neutralizedwith a 2N soda solution (approximately 100 ml). 100 ml ofdichloromethane is added to the medium and the whole is filtered oncelite in order to eliminate the salts in suspension. The organic phaseis extracted, washed 3 times with 50 ml of water, dried, filtered andevaporated to dryness under reduced pressure. The expected product ispurified on silica gel in a dichloromethane/methanol (98/2) mixture andis obtained in the form of of a beige powder (0.6 g, 63%). Meltingpoint: 73-74° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 3.02 (m, 4H, 2CH₂). 3.44 (s, 2H, CH₂). 3.66(wide s, 2H, NH₂), 4.07 (s, 2H, CH₂), 6.62-6.71-7.10-7.27 (4 s, 4H,arom. H).

34.4 [4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide (34)

3-(4-aminobenzyl)-thiazolidine (0.6 g, 3 mmoles) andS-methyl-2-thiophenethiocarboximide hydroiodide (1.14 g, 4 mmoles) areput into solution in 7 ml of an isopropanol/DMF mixture (2/5). Thereaction medium is agitated for 18 hours at ambient temperature. Then 10ml of ethyl acetate is added to the medium and the reaction product isextracted 3 times with 10 ml of water. The aqueous phase is collectedand basified with a saturated solution of sodium hydrogen carbonate,then the product is extracted 3 times with 10 ml of ethyl acetate. It ispurified on silica gel in a dichloromethane/methanol mixture (95/5) andis obtained in the form of a white powder (0.6 g, 65%). Melting point:161.5-163.5° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 2.98 (t, 2H, CH₂), 3.14 (t, 2H, CH₂), 3.54(s, 2H, CH₂), 4.10 (s, 2H, CH₂), 4.85 (wide s, 2H, NH₂), 6.98 (s, 1H,arom. H), 7.00 (s, 1H, arom. H), 7.10 (t, 1H, thiophene), 7.34 (s, 1H,arom. H), 7.36 (s, 1H, arom. H), 7.42 (t, 1H, thiophene), 7.45 (m, 1H,thiophene).

IR: ν_(C═N) (amidine): 1593 cm⁻¹.

Example 35

N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamideFumarate (35)

35.1 1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine

The experimental protocol used is the same as that described forintermediate 33.1. 1,2,3,6-tetrahydropyridine replacing imidazole.Colourless oil.

NMR ¹H (CDCl₃, 100 MHz, δ): 2.33 (m, 2H, CH₂), 3.59 (t, 2H, CH₂), 3.90(m, 2H, CH₂), 5.90 (m, 2H, CH═CH), 6.75-6.82-8.07-8.18 (m, 4H, arom. H).

35.2 1-(4-aminophenyl)-1,2,3,6-tetrahydropyridine

The experimental protocol used is the same as that described forintermediate 34.3, 1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridinereplacing 3-(4-nitrobenzyl)-thiazolidine. Colourless oil.

NMR ¹H (CDCl₃, 100 MHz, δ): 2.31 (m, 2H, CH₂), 3.21 (t, 2H, CH₂), 3.43(m, 2H, NH₂), 3.56 (m, 2H, CH₂), 5.84 (m, 2H, CH═CH), 6.75 (m, 4H, arom.H).

35.3N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamideFumarate (35)

The experimental protocol used is the same as that described forintermediate 33.3. 1-(4-aminophenyl)-1,2,3,6-tetrahydropyridinereplacing 1-(4-aminophenyl)-1H-imidazole. Beige powder. Melting point:193-194° C.

NMR ¹H (DMSO, 400 MHz, δ): 2.23 (m, 2H, CH₂), 3.29 (m, 2H, CH₂), 3.61(m, 2H, CH₂), 5.84 (m, 2H, CH═CH), 6.56 (s, 1H, fumaric acid), 6.89 (m,4H, arom. H), 7.13 (m, 1H, arom. H), 7.67 (m, 1H, arom. H), 7.77 (m, 1H,arom. H).

IR: ν_(C═N) (amidine): 1560 cm⁻¹.

Example 36

N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamideHydrochloride (36)

36.1 1-(4-nitrobenzyl)-1H-imidazole

The experimental protocol used is the same as that described forintermediate 33.1, 1-bromomethyl-4-nitrobenzene replacing1-fluoro-4-nitrobenzene. Colourless oil.

NMR ¹H (CDCl₃, 100 MHz, δ): 5.26 (s, 2H, CH₂), 6.92 (m, 1H, Himidazole), 7.16 (m, 1H, H imidazole), 7.59 (m, 1H, H imidazole),7.24-7.32-8.18-8.27 (4s, 4H, arom. H).

36.2 1-(4-aminobenzyl)-1H-imidazole

The experimental protocol used is the same as that described forintermediate 33.2, 1-(4-nitrobenzyl)-1H-imidazole replacing1-(4-aminophenyl)-1H-imidazole. Pale yellow powder. Melting point:121-122° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 2.87 (wide s, 2H, NH₂), 4.98 (s, 2H, CH₂),6.88 (m, 1H, H imidazole), 7.06 (m, 1H, H imidazole), 7.52 (m, 1H, Himidazole), 6.60-6.69-6.95-7.05 (4s, 4H, arom. H).

36.3 N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamideHydrochloride (36)

The experimental protocol used is the same as that described forintermediate 34.4, 1-(4-aminobenzyl)-1H-imidazole replacing3-(4-aminobenzyl)-thiazolidine. After salification by a molar solutionof HCl in anhydrous diethyl ether, a beige powder is obtained. Meltingpoint: 261-263° C.

NMR ¹H (DMSO, 400 MHz, δ): 5.12 (s, 2H, CH₂), 6.46 (wide s, 2H, NH₂),6.83-6.85-7.22-7.24 (4s, 4H, arom. H), 6.90 (s, 1H, arom. H), 7.09 (t,1H, arom. H), 7.20 (s, 1H, arom. H), 7.60 (d. 1H, arom. H), 7.74 (s, 2H,arom. H).

IR: ν_(C═N) (amidine): 1599 cm⁻¹.

Example 37

N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide (37)

37.1 4-(t-butoxycarbonylamino)-benzeneacetic acid

Para-aminophenylacetic acid (3 g, 20 mmoles) is dissolved in 60 ml of aTHF/H₂O mixture (2/1). 11 ml of 10% soda is added then 6 g ofdi-t-butyl-dicarbonate (28 mmol) in solution in 50 ml of a THF/H₂Omixture (2/1). Agitation is carried out for 18 hours at ambienttemperature. Then the THF is evaporated off under reduced pressure. Themedium is then acidified (pH=2) with a 10% solution of potassium acidsulphate (approximately 45 ml) and the reaction product is extractedwith 3 washings with ethyl acetate (3 times 50 ml). The organic phasesare dried and evaporated in order to produce 4.32 g (87%) of pure4-(t-butoxycarbonylamino)-benzeneacetic acid in the form of a beigepowder. Melting point: 149-150° C. NMR ¹H (CDCl₃, 100 MHz, δ): 1.52 (s,9H, tBu), 3.60 (s, 2H, CH₂), 4.12 (wide s, 1H, COOH), 6.55 (s, 1H, NH),7.21 (m, 4H, arom. H).

37.2 (t-butoxycarbonylamino)-benzene Ethanol

4-(t-butoxycarbonylamino)-benzeneacetic acid (2.9 g, 11.4 mmoles) isdissolved in 10 ml of anhydrous THF at 0° C. and added to a suspensionof LiAlH₄ (0.52 g, 13.6 mmoles) in 30 ml of THF. The reaction mixture isagitated at ambient temperature for 1.5 hours. 50 ml of ethyl acetatethen 20 ml of 2N soda are added to the medium. The expected product isextracted from the organic phase, which is then washed with 3 times 15ml of water. The organic phase is dried and the solvent evaporated offunder reduced pressure. Then the reaction product is purified on silicagel in a dichloromethane/methanol mixture (95/5). 1.1 g (40%) is thusobtained in the form of a colourless oil.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.53 (s, 9H, tBu), 2.82 (t, 2H, CH₂), 3.83(q, 2H, CH ₂-OH), 6.47 (s, 1H, NH), 7.23 (m, 4H, arom. H).

37.3 (2-bromoethyl-4-t-butoxycarbonylamino)benzene

4-(t-butoxycarbonylamino)-benzene ethanol (0.75 g, 3.1 mmoles) andcarbon tetrabromide (1.2 g, 3.6 mmoles) are dissolved in 20 ml ofdichloromethane at 0° C. Triphenylphosphine (0.94 g, 3.6 mmoles) isadded in portions and the whole is agitated for 1 hour at ambienttemperature. The solvent is evaporated off under reduced pressure andthe product obtained is purified on silica gel in an ethylacetate/heptane mixture (1/2),1-(2-bromoethyl-4-t-butoxycarbonylamino)benzene is obtained in the formof a white powder (0.8 g, 84%). Melting point: 129-130° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.52 (s, 9H, tBu), 3.11 (t, 2H, CH₂), 3.54(t, 2H, CH₂Br), 6.45 (s, 1H, NH), 7.22 (m, 4H, arom. H).

37.4 3-[2-[4-(t-butoxycarbonylamino)phenyl]ethyl]thiazolidine

The experimental protocol used is the same as that described forintermediate 34.2, (2-bromoethyl-4-t-butoxycarbonylamino)benzenereplacing 1-bromomethyl-4-nitrobenzene. Colourless oil.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.52 (s, 9H, tBu), 2.90 (m, 8H, 4CH₂), 4.10(s, 2H, N-CH₂—S), 6.46 (s, 1H, NH), 7.25 (m, 4H, arom. H).

37.5 3-{2-[4-aminophenyl]ethyl}thiazolidine

2.3 g (20 mmoles) of trifluoroacetic acid is added to a 100 ml flaskcontaining a solution of 616 mg (2 mmoles) of intermediate 5.4 in 10 mlof dichloromethane. After agitation for one hour at 20° C. the reactionmixture is concentrated to dryness under vacuum. The residue is dilutedwith a mixture of 20 ml of dichloromethane and 20 ml of 4N soda. Afterdecantation, the organic phase is washed successively with 3×20 ml ofwater followed by 20 ml of salt water. The organic solution is driedover sodium sulphate, filtered and the solvent is evaporated off underreduced pressure in order to obtain a colourless oil with a yield of72%.

NMR ¹H (CDCl₃, 100 MHz, δ): 2.85 (m, 8H, 4CH₂), 4.15 (s, 2H, N-CH₂—S),7.25 (m, 4H, arom. H).

37.6 [4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide(37)

The experimental protocol used is the same as that described forintermediate 2.4, 3-{2-[4-aminophenyl]ethyl}thiazolidine replacing3-(4-aminobenzyl)-thiazolidine. Beige powder. Melting point: 60.5-61.5°C.

NMR ¹H (DMSO, 400 MHz, δ): 2.65 (t, 2H, CH₂), 2.82 (t, 2H, CH₂), 2.91(t, 2H, CH₂), 3.13 (t, 2H CH₂), 4.13 (s, 2H, N—CH₂S),6.93-6.95-7.19-7.21 (4s, 4H, arom. H), 7.09 (t, 1H, H thiophene), 7.44(m, 2H, H thiophene). IR: ν_(C═N) (amidine): 1591 cm⁻¹.

Example 38

N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamideHydroiodide (38)

38.1 1-{2-[4-(t-butoxycarbonylamino)phenyl]ethyl}-1H-imidazole

2.5 g (18 mmoles) of K₂CO₃ is mixed together in a 100 ml flask with 680mg (10 mmoles) of imidazole diluted in 10 ml of acetonitrile. Thereaction mixture is heated at 70° C. before the dropwise addition of asolution of 2 g (9.2 mmoles) of 1-bromomethyl-4-nitrobenzene in solutionin 25 ml of acetonitrile. After agitation for 2 hours at thistemperature, the reaction mixture is cooled down and filtered in orderto eliminate the insoluble part. The filtrate is concentrated undervacuum and the residue is diluted in 50 ml of dichloromethane. Theorganic solution is successively washed with 3×50 ml of water and 50 mlof salt water. After drying over Na₂SO₄, filtration, the organic phaseis concentrated under vacuum and the residue purified on a silica column(eluant: dichloromethane/methanol: 95/5). Brown oil.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.50 (s, 9H, tBu), 2.90 (t, 2H, CH₂), 4.10(t, 2H, CH₂), 6.50 (s, 1H, NH), 7.05 (m, 4H, arom. H), 6.85 (m, 1H, Himidazole), 7.03 (s, 1H, H imidazole), 7.32 (m, 1H, H imidazole).

38.2 1-[2-(4-aminophenyl)ethyl]-1H-imidazole

The experimental protocol used is the same as that described forintermediate 37.5,1-{2-[4-(t-butoxycarbonylamino)phenyl]ethyl}-1H-imidazole replacing3-{2-[4-(t-butoxycarbonyl amino)phenyl]ethyl}thiazolidine. Colourlessoil.

NMR ¹H (CDCl₃, 100 MHz, δ): 2.90 (t, 2H, CH₂), 3.35 (wide s, 2H, NH₂),4.10 (t, 2H, CH₂), 6.70 (m, 4H, arom. H), 6.85 (m, 1H, H imidazole.),7.03 (s, 1H, H imidazole.), 7.32 (m, 1H, H imidazole).

38.3 N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamideHydroiodide (38)

The experimental protocol used is the same as that described forintermediate 33.3, 1-[2-(4-aminophenyl)ethyl]-1H-imidazole replacing1-(4-aminophenyl)-1H-imidazole. Beige powder. Melting point: 214-215° C.

NMR ¹H (DMSO, 400 MHz, δ): 3.11 (t, 2H, CH₂), 4.33 (t, 2H, CH₂), 7.29(m, 6H. arom. H), 7.99 (m, 1H, arom. H), 8.70 (wide s, 2H, NH₂).

IR: νC_(═N) (amidine): 1597 cm⁻¹.

Example 39

N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamideFumarate (39)

39.11-{2-[4-(t-butoxycarbonylamino)phenyl]ethyl}-1,2,3,6-tetrahydropyridine

The experimental protocol used is the same as that described forintermediate 38.1, 1,2,3,6-tetrahydropyridine replacing thiazolidine.Colourless oil.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.57 (s, 9H, tBu), 2.10 (m, 2H, CH₂), 2.70(m, 6H, 3CH₂), 3.00 (m, 2H, CH₂), 5.72 (m, 2H, CH═CH), 6.48 (s, 1H, NH),7.10 (m, 4H, arom. H).

39.2 1-[2-(4-aminophenyl)ethyl]-1,2,3,6-tetrahydropyridine

The experimental protocol used is the same as that described forintermediate 37.5,1-{2-[4-(t-butoxycarbonylamino)phenyl]ethyl}-1,2,3,6-tetrahydropyridinereplacing 3-{2-[4-aminophenyl]ethyl}thiazolidine. Colourless oil.

NMR ¹H (CDCl₃, 100 MHz, δ): 3.20 (m, 2H, CH₂), 3.80 (m, 6H, 3CH₂), 4.10(m, 2H, CH₂), 4.57 (wide s, 2H, NH₂), 6.90 (m, 2H, CH═CH), 8.00 (m, 4H,arom. H).

39.3N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamideFumarate (39)

The experimental protocol used is same as that described forintermediate 33.3. 1-[2-(4-aminophenyl)ethyl]-1,2,3,6-tetrahydropyridinereplacing 1-(4-aminophenyl)-1H-imidazole.White powder. Melting point:128-129° C.

NMR ¹H (DMSO, 400 MHz, δ): 2.19 (m, 2H, CH₂), 2.83 (m, 6H, 3CH₂), 3.25(m, 2H, CH₂), 5.72 (m, 2H, CH═CH), 6.58 (s, 3H. fumaric acid),6.81-6.83-7.18-7.20 (4s, 4H, arom. H), 7.10 (t, 1H, H thiophene), 7.63(m, 1H, H thiophene), 7.75 (m, 1H, H thiophene).

IR: ν_(C═N) (amidine): 1620 cm⁻¹.

Example 40

N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide(40)

40.1 3-[{4-(t-butoxycarbonylamino)phenyl}methylcarbonyl]thiazolidine

4-(t-butoxycarbonylamino)-benzeneacetic acid (1.4 g, 5.6 mmoles).intermediate 37.1. and carbonyldiimidazole (0.9 g, 5.6 mmoles) aredissolved in 15 ml of THF. The reaction is maintained at ambienttemperature for 1 hour. Then thiazolidine (0.5 g, 5.6 mmol). in solutionin THF (5 ml), is added to the medium. The whole is agitated again for 2hours at ambient temperature. The solvents are evaporated off underreduced pressure. Then the residue is taken up in 25 ml ofdichloromethane and washed 3 times with 15 ml of water. The organicphase is dried and concentrated under reduced pressure.3-[{4-(t-butoxycarbonylamino)phenyl}methylcarbonyl]thiazolidine isobtained in the form of a white powder (1.43 g, 79%) and will be usedwithout further purification in the following stages. Melting point:223-224° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.51 (s, 9H, tBu), 3.00 (m, 2H, CH₂—S), 3.67(s, 2H, N—CH₂—S), 3.88 (m, 2H, CH₂—N), 4.52 (d, J=16 Hz, 2H, CH₂—CO),6.52 (wide s, 1H, NH), 7.26 (m, 4H, arom. H).

40.2 3-[(4-aminophenyl)methylcarbonyl]thiazolidine

3-[(4-aminophenyl)methylcarbonyl]thiazolidine is obtained in the form ofa colourless oil with a yield of 44% by following the operating methoddescribed for intermediate 37.5.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.62 (wide s, 2H, NH₂), 2.98 (m, 2H, CH₂—S),3.61 (s, 2H, N—CH₂—S), 3.80 (m, 2H, CH₂—N), 4.52 (d. J=16 Hz. 2H,CH₂—CO), 6.61-6.69-7.01-7.09 (4 s, 4H, arom. H).

40.3[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide(40)

The operating method used is the same as that described for intermediate34.4, 3-[(4-aminophenyl)methylcarbonyl]thiazolidine replacing3-(4-aminobenzyl)-thiazolidine. The free base is obtained with a yieldof 64%. Melting point: 163.0-163.5° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 3.01 (m, 2H, CH₂—S), 3.69 (d, J=6 Hz. 2H,N—CH₂—S), 3.75-3.88 (2 t, 2H, CH₂—N), 4.55 (d, 2H, CH₂—CO), 4.87 (s, 2H,NH₂), 6.95-6.97-7.22-7.24 (4 s, 4H, arom. H), 7.08 (t, 1H, thiophene),7.43 (m, 2H, thiophene).

IR: ν_(C═O) (amide): 1630 cm⁻¹; ν_(C═N) (amidine): 1577 cm⁻¹.

Example 41

N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamideFumarate (41)

41.1 3-(t-butoxycarbonyl)thiazolidine-2-carboxylic Acid

Thiazolidine-2-carboxylic acid (2 g, 15 mmoles) is agitated in thepresence of di-t-butyl dicarbonate according to the operating methoddescribed for intermediate 37.1.3-(t-butoxycarbonyl)thiazolidine-2-carboxylic acid is obtained in theform of a pale yellow oil with a yield of 97% (3.4 g) and will be usedas is in the following stages.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.46 (s, 9H, tBu), 3.10 (m, 3H. CH₂—S,CH—S), 3.85 (m, 2H, CH₂—N).

41.2 (4-nitrobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide

3-(t-butoxycarbonyl)thiazolidine-2-carboxylic acid (1 g, 4.3 mmol) andcarbonyldiimidazole (0.7 g, 4.3 mmol) are dissolved in THF (10 ml). themixture is agitated for 1 hour at ambient temperature.4-nitrobenzylamine (0.81 g, 4.3 mmoles) and triethylamine (0.6 ml. 0.43g, 4.3 mmoles) in suspension in 10 ml of a THF and DMF mixture (1/1) areadded to the preceding solution and the whole is heated under reflux for5 hours. The solvents are then evaporated off under reduced pressure.The residue is taken up in 25 ml of ethyl acetate and washed 3 timeswith 15 ml of water. The organic phase is dried and the solvent isevaporated off under reduced pressure. The product obtained is purifiedon silica gel in a dichloromethane/methanol mixture (95/5).N-(4-nitrobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide isobtained in the form of a pale yellow oil with a yield of 80% (1.25 g).

NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 3.09 (m, 3H, CH₂—S,CH—S), 3.86 (m, 2H, CH₂—CH₂ —N), 4.57 (m, 2H, CH₂—NH), 6.60 (wide s, 1H,NH), 7.41-7.50-8.14-8.23 (4s, 4H, arom. H).

41.3 (4-aminobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide

A spatula tip's worth of Nickel of Raney is added to a solution of 1.25g (3.4 mmoles) ofN-(4-nitrobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide in 2.5ml of methanol. The whole is taken to reflux and hydrazine hydrate (1.75ml) is added dropwise to the medium. The reaction is maintained for 1hour under reflux, then returned to ambient temperature. The catalyst isfiltered off and abundantly rinsed with methanol. The solvent isevaporated off under reduced pressure. Then the residue is taken up indichloromethane (20 ml) and washed 3 times with 15 ml of water. Theorganic phase is dried and the solvent is evaporated off under reducedpressure.N-(4-aminobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide isobtained in the form of an inert yellow solid (0.815 g, 71%); it will beused in following stages without further purification.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.43 (s, 9H, tBu), 3.08 (m, 2H, CH₂—S), 3.67(m, 3H, CH₂—CH₂ —N, CH—S), 4.36 (m, 2H, CH₂—NH), 6.05 (wide s, 1H, NH),6.60-6.69-7.04-7.12 (4 s, 4H, arom. H).

41.4[4-{[3-(t-butoxycarbonyl)-2-thiazolidinyl]carbonylaminomethyl}phenyl]-2-thiophenecarboximidamide

The experimental protocol used is the same as that described forintermediate 34.4,N-(4-aminobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamidereplacing 3-(4-aminobenzyl)-thiazolidine. The expected compound isobtained with a yield of 77%.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 3.14 (m, 3H, CH₂—S,CH—S), 3.84 (m, 2H, CH₂—CH₂ —N), 4.46 (m, 2H, CH₂—NH), 4.83 (wide s, 2H,NH₂), 6.27 (wide s, 1H, NH), 7.22 (m, 7H, arom. H).

41.5N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamideFumarate (41)

The experimental protocol used is the same as that described forintermediate 37.5.[4-{[3-(t-butoxycarbonyl)-2-thiazolidinyl]carbonylaminomethyl}phenyl]-2-thiophene-carboximidamidereplacing 3-{2-[4-aminophenyl]ethyl}thiazolidine. The expected compoundis obtained in the form of the free base with a yield of 34%. It issalified with an equivalent of fumaric acid in ethanol under reflux.Melting point: 167-168° C.

NMR ¹H (DMSO, 400 MHz, δ): 2.78 (t, 2H, CH₂—S), 3.06 (m, 2H, CH₂—CH₂—N), 3.28 (wide s, 1H, CH—S), 4.26 (m, 2H, CH₂—NH), 4.86 (wide s, 1H,NH), 6.45 (wide s, 2H, NH₂), 6.81-6.83-7.19-7.21 (4 s, 4H, arom. H),7.10 (t, 1H, thiophene), 7.61 (d. 1H, thiophene), 7.74 (m, 1H,thiophene), 8.53 (t, 1H, NH—CO). IR: ν_(C═O) (amide): 1624 cm^(−1;)ν_(C═N) (amidine): 1584 cm⁻¹.

Example 42

N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furanCarboxamide Hydroiodide (42)

42.1 2,6-di-t-butyl-4-nitrophenol

2,6-di-t-butylphenol (8 g, 39 mmoles) is dissolved in 25 ml ofcyclohexane at 10° C. A (1/1) mixture of nitric acid/acetic acid (5 ml)is added dropwise to the reaction medium maintained at this temperature.Agitation is then carried out for 15 minutes at ambient temperature.Then the precipitate formed is filtered off, rinsed with water andpentane. The 2,6-di-t-butyl-4-nitrophenol obtained (6.34 g, 65%) isdried in an oven and will be used without further purification in thefollowing stages. Pale yellow powder. Melting point: 167-168° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.48 (s, 18H, 2tBu), 5.93 (s, 1H, OH), 8.13(s, 2H, arom. H).

42.2 2,6-di-t-butyl-4-aminophenol

2,6-di-t-butyl-4-nitrophenol (6.3 g, 25 mmoles) is dissolved in methanol(100 ml), 0.6 g of palladium on carbon (10%) is added and the reactionmedium is placed under a hydrogen atmosphere under 2 bars of pressure.The catalyst is filtered out and the solvent is evaporated off underreduced pressure. The residue is taken up in heptane and filtered. Inthis way 2,6-di-t-butyl-4-aminophenol (2.7 g, 48%) is obtained whichwill be used without further purification in the following stages. Pinkpowder. Melting point: 123-124° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 6.60 (s, 2H, Ph); 4.65 (wide s, 1H, OH);3.15 (wide s, 2H, NH₂); 1.42 (s, 18H, 2 tBu).

42.3 N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-nitrophenyl)-2-furanCarboxamide

The experimental protocol used is the same as that described forintermediate 40.1, 2,6-di-t-butyl-4-aminophenol and5-(4-nitrophenyl)-2-furan carboxylic acid replacing thiazolidine and4-(t-butoxycarbonylamino)-benzeneacetic acid respectively. The expectedcompound is obtained in the form of a colourless oil with a yield of56%.

RMN¹H (DMSO, 100 MHz, δ): 1.41 (s, 18H, 2tBu), 6.91 (s, 1H, OH), 7.42(m, 4H, arom. H), 7.54 (s, 2H, arom. H), 8.30 (m, 4H, arom. H), 10.11(s, 1H, NH).

42.4 N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-aminophenyl)-2-furanCarboxamide

The experimental protocol used is the same as that described forintermediate 1.2.N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-nitrophenyl)-2-furan carboxamidereplacing 1-(4-nitrophenyl)-1H-imidazole. The expected compound isobtained in the form of a colourless oil with a yield of 59%.

NMR ¹H (DMSO, 100 MHz, δ): 1.41 (s, 18H, 2 tBu), 4.70 (wide s, 2H, NH₂),6.91 (s, 1H, OH), 7.50 (m, 4H, arom. H), 7.54 (s, 2H, arom. H), 8.20 (m,4H, arom. H).

42.5N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furanCarboxamide Hydroiodide (42)

The experimental protocol used is the same as that described forintermediate 33.3,N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-aminophenyl)-2-furan carboxamidereplacing 1-(4-aminophenyl)-1H-imidazole. The expected product isobtained in salified form with a yield of 27%. Melting point: 273-274°C.

NMR ¹H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2tBu), 6.90 (s, 1H, OH), 7.45(m, 5H, arom. H), 7.54 (s, 2H, arom. H), 8.15 (m, 4H, arom. H),9.05-9.90 (wide 2s's, 2H, NH₂), 10.01 (s, 1H, NH—CO), 11.57 (s, 1H, HI).

IR: ν_(OH): 3423-3242 cm⁻¹; ν_(C═O) (amide): 1646 cm⁻¹; ν_(C═N)(amidine): 1554 cm⁻¹.

Example 43

3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedioneHydrochloride (43)

43.1 Ethyl (3,5-di-t-butyl-4-hydroxyphenyl)amino Acetate

1 g (4.5 mmol) of 2,6-di-t-butyl-4-aminophenol (intermediate 10.2) and0.65 g of sodium acetate (7.9 mmol) are put into suspension in 1 ml ofethanol. Then bromoethyl acetate (0.94 g, 5.65 mmol) is added to themedium and the reaction medium is heated at 65° C. for 2 hours. Thereaction mixture is poured into 20 ml of ice-cooled water and thereaction product is extracted with dichloromethane (3 times 15 ml). Theorganic phases are dried and the solvent is evaporated off under reducedpressure. The residue is passed over silica gel in dichloromethane. Acolourless oil is obtained constituted by a mixture of 2 compounds: theproduct of mono- and di-substitution. The mixture of these 2 compoundsis used without further purification in the following stage.

43.2 Ethyl(3,5-di-t-butyl-4-hydroxyphenyl)-(4-nitrophenylcarbamoyl)amino Acetate

1.13 g (4.2 mmoles) of intermediate 43.1 and 0.69 g (4.23 mmoles) of4-nitrophenylisocyanate are dissolved in 9 ml of dichloromethane. Thereaction mixture is agitated for 2.5 hours at ambient temperature. Thesolvent is evaporated off under reduced pressure and the residue ispassed over silica gel in dichloromethane. In this way 0.66 g of pure(3,5-di-t-butyl-4-hydroxyphenyl)-(4-nitrophenylcarbamoyl)aminoethylacetate is isolated in the form of a colourless oil. (Yield over 2stages: 31%).

NMR ¹H (CDCl₃, 100 MHz, δ): 1.30 (t, 3H, CH₃), 1.46 (s, 18H, 2tBu), 4.23(q, 2H, CH₂ —CH₃), 4.38 (s, 2H, CH₂—CO), 5.50 (s, 1H, OH), 6.75 (wide s,1H, NH), 7.28 (s, 2H, arom. H), 7.40-7.50-8.10-8.20 (4s, 4H, arom. H).

43.3(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-nitrophenyl)-2,5-imidazolidinedione

0.66 g (1.4 mmole) of intermediate 43.2 is dissolved in 10 ml of ethanolat 50° C. and the whole is heated at this temperature for 2 hours. Theprecipitate formed is filtered off and washed with cold ethanol. Thecompound obtained is used directly in the following stage withoutadditional purification.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.47 (s, 18H, 2tBu), 4.51 (s, 2H, N—CH₂—CO),5.27 (s, 1H, OH), 7.33 (s, 2H, arom. H), 7.77-7.86-8.32-8.41 (4s, 4H,arom. H).

43.4(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-aminophenyl)-2,5-imidazolidinedione

The experimental protocol used is the same as that described forintermediate 33.2,3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-nitrophenyl)-2,5-imidazolidinedionereplacing 1-(4-nitrophenyl)-1H-imidazole. The expected compound isobtained in the form of a white precipitate with a yield of 87%. It isused without additional purification in the following stage.

NMR ¹H (CDCl₃, 100 MHz): 1.47 (s, 18H, 2tBu), 4.45 (s, 2H, N—CH₂—CO),5.18 (s, 1H, OH), 6.70-6.80-7.16-7.23 (4s, 4H, arom. H), 7.39 (s, 2H,arom. H).

43.53-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedioneHydrochloride (43)

The experimental protocol used is the same as that described forintermediate 34.4,3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-aminophenyl)-2,5-imidazolidinedionereplacing 3-(4-aminobenzyl)-thiazolidine. The free base is salified bytreatment with a 1N solution of hydrochloric ether. The hydrochloride isobtained with a yield of 53%. Melting point: 258-265° C.

NMR ¹H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 4.65 (s, 2H, CH₂), 7.08(s, 1H, OH), 7.40 (m, 3H, arom. H), 7.61 (s, 4H, arom. H), 8.21 (m, 2H,arom. H), 9.20-9.95 (wide 2s's, 2H, NH₂), 11.75 (s, 1H, HCl).

IR: ν_(OH): 3637-3437 cm⁻¹; ν_(C═O) (imidazolidinedione): 1712 cm⁻¹;ν_(C═O) (amidine): 1598 cm⁻¹.

Example 44

2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinoneHydrochloride (44)

44.12-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone

5 g of 3,5-di-t-butyl-4-hydroxybenzaldehyde (21 mmol) and 2.95 g ofpara-nitroaniline (21 mmol) are dissolved in 50 ml of anhydrous toluene.0.5 ml of glacial acetic acid is added and the whole is taken to refluxfor 24 hours. Then 1.96 g of mercaptoacetic acid (21 mmol) is added tothe medium and reflux is continued for another 24 hours. After thereaction mixture has returned to ambient temperature, it is washed withwater (3 times 30 ml). After decantation, the organic phase is driedover sodium sulphate and the solvent is evaporated off under reducedpressure. The residue is purified on silica gel in an ethylacetate/heptane mixture (1/4) and 1.33 g of pure2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone isobtained in the form of a colourless oil (15%).

NMR ¹H (CDCl₃, 100 MHz, δ): 1.36 (s, 18H, 2tBu), 3.91 (s, 2H, CH—S),5.28 (s, 1H, CH—S), 6.20 (s, 1H, OH), 7.03 (s, 2H, arom. H),7.38-7.48-8.11-8.20 (4 s, 4H, arom. H).

44.22-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinone

1.3 g of2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone (3mmol) and 3.4 g (15 mmol) of dihydrated tin chloride are dissolved in 25ml of ethyl acetate. The reaction is maintained for 2 hours at 70° C.After the mixture has returned to ambient temperature, it is poured intoa saturated solution of sodium hydrogen carbonate. The expected productis then extracted from the organic phase then it is washed 3 times with10 ml of water. The2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinone ispurified on silica gel in an ethyl acetate/heptane mixture (1/1) and isobtained in the form of a beige oil with a yield of 69% (0.82 g).

NMR ¹H (CDCl₃, 100 MHz, δ): 1.37 (s, 18H, 2tBu), 3.64 (wide s, 2H, NH₂),3.89 (s, 2H, CH₂—S), 5.22 (s, 1H, CH—S), 5.91 (s, 1H, OH),6.51-6.59-6.78-6.86 (4 s, 4H, arom. H), 7.04 (s, 2H, arom. H).

44.32-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinoneHydrochloride (44)

The experimental protocol used is the same as that described forintermediate 34.4,2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinonereplacing 3-(4-aminobenzyl)-thiazolidine. The expected compound isobtained in salified form (hydrochloride) by treatment of the free basewith a 1N solution of hydrochloric ether with a yield of 43%. Meltingpoint: 58-61° C.

NMR ¹H (DMSO, 400 MHz, δ): 1.32 (s, 18H, 2tBu), 3.93 (m, 2H, CH—S), 6.57(s, 1H, CH—S), 7.08 (s, 2H, arom. H), 7.41 (m, 5H, arom. H), 8.15 (m,2H, arom. H), 9.10-9.90 (wide 2s's, 2H, NH₂), 11.45 (wide s, 1H, HCl).

IR: ν_(OH): 3624-3423 cm⁻¹; ν_(C═O) (thiazolidinone): 1679-1658 cm⁻¹;ν_(C═N) (amidine): 1568 cm⁻¹.

Example 45

5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedioneFumarate (45)

45.1 1-Methyl-3-(4-nitrophenyl)-2,4-imidazolidinedione

0.47 g of the ethyl ester of sarcosine, HCl (3 mmoles) is dissolved in 5ml of dichloromethane and 0.42 ml (3 mmoles) of triethylamine is added.0.5 g of 4-nitrophenylisocyanate (3 mmoles) in solution in 5 ml ofdichloromethane is added dropwise in the preceding mixture and thereaction mixture is maintained for 30 minutes at ambient temperature.The organic solution is then washed with water (3 times 10 ml) thendried and the solvent is evaporated off under reduced pressure. Theresidue is taken up in 10 ml of ethanol and the reaction medium isheated under reflux for 2 hours. After the reaction medium has returnedto ambient temperature, the precipitate formed is filtered. In this way1-methyl-3-(4-nitrophenyl)-2,4-imidazolidinedione is obtained with ayield of 72% (0.5 g) and will be used without further purification inthe following stage.

NMR ¹H (CDCl₃, 100 MHz, δ): 3.11 (s, 3H, CH₃), 4.09 (s, 2H, CH₂),7.70-7.79-8.27-8.37 (4 s, 4H, arom. H).

45.25-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-nitrophenyl)-2,4-imidazolidinedione

Intermediate 45.1 (0.5 g, 2.13 mmol),3,5-di-t-butyl-4-hydroxybenzaldehyde (0.5 g, 2.13 mmol) and β-alanine(0.123 g, 1.4 mmol) are dissolved in acetic acid (10 ml). The reactionis maintained under reflux for 24 hours. After the reaction medium hasreturned to ambient temperature, 40 ml of water is added to the mediumand the whole is agitated for 1 hour. The precipitate formed is filteredand washed with water. The filtrate is concentrated under vacuum and theevaporation residue is purified on silica gel (eluant: heptane/ethylacetate: 4/1). The pure fractions are collected and concentrated todryness in order to produce the expected product with a yield of 32%(0.3 g).

NMR ¹H (CDCl₃, 100 MHz, δ): 1.49 (s, 18H, 2tBu), 3.35 (s, 3H, CH₃), 5.59(s, 1H, OH), 6.40 (s, 1H, CH═C), 7.75-7.84-8.31-8.40 (4 s, 4H, arom. H),7.92 (s, 2H, arom. H).

45.35-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-aminophenyl)-2,4-imidazolidinedione

The experimental protocol used is the same as that described forintermediate 44.2,5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-nitrophenyl)-2,4-imidazolidinedionereplacing2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone.The expected compound is obtained with a yield of 45%.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.47 (s, 18H, 2tBu), 3.30 (s, 3H, CH₃), 5.51(s, 1H, OH), 6.28 (s, 1H, CH═C), 6.69-6.78-7.12-7.21 (4 s, 4H, arom. H),7.91 (s, 2H, arom. H).

45.45-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedioneFumarate (45)

The experimental protocol used is the same as that described forintermediate 34.4,5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-aminophenyl)-2,4-imidazolidinedionereplacing 3-(4-aminobenzyl)-thiazolidine. The expected compound isobtained in salified form (fumarate) by treatment of the free base withan equivalent of fumaric acid in ethanol while warm with a yield of 35%.Melting point: 54.5-57.5° C.

NMR ¹H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2tBu), 3.22 (s, 3H, CH₃), 6.59(s, 1H, CH═C), 6.61 (s, fumaric acid), 6.97-6.99-7.30-7.32 (4 s, 4H,arom. H), 7.11 (t, 1H, thiophene), 7.64 (d, 1H, thiophene), 7.79 (m, 1H,thiophene), 7.96 (s, 2H, arom. H).

IR: ν_(OH): 3618-3433 cm⁻¹; ν_(C═O) (imidazolidinedione): 1711 cm⁻¹;ν_(C═N) (amidine): 1585 cm⁻¹.

Example 46

2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamideHydrochloride (46)

46.1 Methyl Ester of2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-4-(4-nitrophenoxy)-proline

A solution of 4.37 g (30.7 mmoles) of 4-nitrophenol in 30 ml ofanhydrous N-methyl-2-pyrrolidinone is added slowly to a suspension,cooled down to 0° C., of 1.23 g (30.7 mmol) of NaH at 60% in suspensionin 30 ml of anhydrous N-methyl-2-pyrrolidinone, under an inertatmosphere. After agitation for one hour at 0° C., the prolinederivative (6 g, 15 mmol) is added in one go. The reaction mixture isagitated at 20° C. for 15 hours followed by heating at 80° C. for 2hours in order to complete the reaction. After the reaction mixture hasreturned to 20° C., 200 ml of ethyl acetate and 100 ml of 1N soda areadded to the medium. After decantation, the organic phase is washedsuccessively with dilute solutions of 1N soda until complete extractionof the unreacted phenolic derivative, 2×100 ml of water and 100 ml ofsalt water. The organic solution is dried over sodium sulphate, filteredand concentrated to dryness under reduced pressure, in order to producea light yellow oil which crystallizes spontaneously in air. The crystalsare collected and washed with 3×50 ml of ethyl ether. After drying,colourless crystals are obtained with a yield of 63%. Melting point:155-157° C.

NMR ¹H (DMSO, 400 MHz, δ): 1.34-1.40 (2s, 9H, tBu); 2.45 (m, 2H, CH₂);3.60 (m, 2H, CH₂—N); 3.58-3.63 (2s, 3H, O—CH₃); 4.40 (m, 1H, CH—CO₂);5.22 (m, 1H, HC—O); 7.63 (m, 4H, Ph).

46.22-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-4-(4-nitrophenoxy)-proline

730 mg (approximately 16 mmol) of potash diluted in 5 ml of water isadded at 20° C. to a 100 ml flask containing 2.87 g (7.84 mmol) ofcompound 46.1 in 40 ml of ethanol. After agitation for 15 hours, thereaction mixture is diluted with 100 ml of ethyl acetate, acidified at0° C. with a 12N solution of HCl and decanted. The organic phase iswashed with 50 ml of water followed by 50 ml of salt water. After dryingover sodium sulphate, the organic solution is filtered and concentratedto dryness under vacuum. 2.67 g of a white powder is obtained which isused directly in the following stage without additional purification.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.50 (s, 9H, tBu); 2.60 (m, 2H, CH₂); 3.80(m, 2H, CH₂—N); 4.60 (m, 1H, CH—CO₂); 5.07 (m, 1H, HC—O); 7.58 (m, 4H,Ph); 8.95 (wide s, 1H, CO₂H).

46.32-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-(4-nitrophenoxy)-prolinamide

1.28 g (6.20 mmol) of dicyclohexylcarbodiimide is added at 0° C. to asolution of 1.99 g (5.64 mmol) of intermediate 46.2, 1.25 g (5.64 mmol)of intermediate 42.2 and 845 mg (6.20 mmol) of hydroxybenzotriazole in25 ml of DMF. After agitation for 24 hours at 20° C., the reactionmixture is filtered and the precipitate is washed with ethyl acetate.The filtrate is diluted with 100 ml of ethyl acetate and washedsuccessively with 2×40 ml of 1N soda, 2×40 ml of water and 40 ml of saltwater. After drying over sodium sulphate, the organic solution isfiltered and concentrated to dryness under vacuum in order to produce abrown oil which is purified on a silica column (eluant heptane/ethylacetate: 1/1). The pure fractions are collected and after concentrationunder vacuum, 1.35 g (43%) of a beige powder is obtained. Melting point:117-120° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.20-1.70 (m, 27 H, 3×tBu); 2.68 (m, 2H,CH₂); 3.80 (m, 2H, CH₂—N); 4.58 (m, 1H, CH—CO₂); 5.10 (m, 2H, OH, HC—O);7.25-7.28 (2s, 2H, Ph-OH); 7.51 (m, 4H, Ph-NO₂); 8.00 (wide s, 1H,NHCO).

46.42-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-(4-aminophenoxy)-prolinamide

1.35 g (2.4 mmol) of intermediate 46.3 in 30 ml of ethanol is dissolvedin an autoclave equipped with a magnetic stirrer in the presence of ½ aspatula's worth of Pd/C at 10%. The reaction mixture is agitated under1.5 bar of hydrogen for 3 hours. After filtration on celite, thefiltrate is concentrated under vacuum. The residue is taken up in a 1/1ethyl ether/heptane mixture and after crystallization, it is filteredand rinsed using heptane. A beige powder is obtained with a yield of60%. Melting point: 112-113° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.20-1.70 (m, 27 H, 3×tBu); 2.55 (m, 2H,CH₂); 3.50 (wide s, 2H, NH₂); 3.75 (m, 2H, CH₂—N); 4.48 (m, 1H, CH—CO₂);4.80 (m, 1H, HC—O); 5.10 (s, 1H, OH); 6.65 (m, 4H, Ph-NH₂); 7.28 (m, 2H,Ph-OH); 8.00 (wide s, 1H, NHCO).

46.52-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-{4-[(imino(2-thienyl)methyl)amino}phenoxy]-prolinamideHydrochloride (46)

A mixture of 694 mg (1.32 mmol) of intermediate 46.4 is heated at 50° C.for 48 hours in the presence of 376 mg (1.32 mmol) ofS-methyl-2-thiophenethiocarboximide hydroiodide in solution in 15 ml ofisopropanol. The reaction mixture is then concentrated to dryness undervacuum and the evaporation residue is suspended in 50 ml of ethylacetate. After the addition of 50 ml of a saturated solution of Na₂CO₃the organic phase is decanted and successively washed with 25 ml of asaturated solution of Na₂CO₃, 50 ml of water and 50 ml of salt water.After drying over sodium sulphate, the organic solution is filtered andconcentrated to dryness under vacuum in order to produce a yellow powderwhich is purified on a silica column (eluant: ethyl acetate). The purefractions are collected and after concentration under vacuum. 686 mg(82%) of a beige powder is obtained which is immediately dissolved in 5ml of a 4M solution of HCl in 1,4-dioxan. After agitation for 15 hoursat 20° C., 20 ml of dry ethyl ether is added to the reaction mixture.The precipitate which appears is then filtered off, rinsed with 2×25 mlof dry ethyl ether and dried in an oven in order to produce 270 mg of abeige powder. Melting point: 233.5-235° C.

NMR ¹H (DMSO, 400 MHz, δ): 1.37 (s, 18H, 2×tBu); 2.61 (m, 2H, CH₂); 3.60(m, 2H, CH₂—N); 4.56 (m, 1H, CH—CO₂); 5.25 (m, 1H, HC—O); 6.92 (s, 1H,OH); 7.21 (m, 4H, Ph-N); 7.38 (m, 1H, thiophene); 7.45 (s, 2H, Ph-OH);8.18 (m, 2H, thiophene); 8.78 (wide s, 1H, NH⁺); 9.09 (wide s, 1H, NH⁺);9.80 (wide s, 1H, NH⁺); 10.68 (c. 1H, CONH); 11.42 (wide s, 1H, NH⁺).

IR: ν_(OH): 3624-3420 cm⁻¹; ν_(C═O) (amide): 1653 cm⁻¹; n_(C═N)(amidine): 1610 cm⁻¹.

Example 47

5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridineCarboxamide Hydrochloride (47)

47.1 5,6-dihydro-N-(4-nitrophenyl)-1-(2H)-pyridine Carboxamide

900 mg (5 mmol) of 4-nitrophenylisocyanate is dissolved, under an argonatmosphere, in a 100 ml three-necked flask in 17 ml of dry DMF. 0.45 ml(5 mmol) of 1,2,3,6-tetrahydropyridine is added to this solution in onego, and agitation is maintained for 15 hours. The reaction mixture isthen concentrated to dryness under vacuum and the evaporation residueplaced on a silica gel column. After elution with a heptane/ethylacetate mixture: 4/6, the pure fractions are collected and concentratedunder reduced pressure in order to produce 860 mg (70%) of a brightyellow powder. Melting point: 169-170° C.

NMR ¹H (DMSO, 100 MHz, δ): 2.29 (m, 2H, ═CH—CH₂); 3.69 (m, 2H, CH₂—N);4.10 (m, 2H, ═CH—CH₂—N); 5.91 (m, 2H, CH═CH); 8.09 (m, 4H, Ph); 9.32(wide s, 1H, NHCO).

47.2 N-(4-aminophenyl)-5,6-dihydro-1-(2H)-pyridine Carboxamide

The experimental protocol used is the same as that described forintermediate 44.2, 5,6-dihydro-N-(4-nitrophenyl)-1-(2H)-pyridinecarboxamide replacing2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone. Abrown oil is obtained with a yield of 36%.

NMR ¹H (CDCl₃+D₂O, 400 MHz, δ): 2.20 (m, 2H, ═CH—CH₂); 3.59 (m, 2H,CH₂—N); 3.95 (m, 2H, ═CH—CH₂—N); 5.84 (m, 2H, CH═CH); 6.90 (m, 4H, Ph);9.32 (wide s, 1H, NHCO).

47.35,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridineCarboxamide Hydrochloride (47)

The experimental protocol used is the same as that described forintermediate 46.5, N-(4-aminophenyl)-5,6-dihydro-1-(2H)-pyridinecarboxamide replacing2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-(4-aminophenoxy)-prolinamide.After salification, using a solution of 1M HCl in ethyl ether, a paleyellow powder is obtained with a yield of 55%. Melting point: 230-231°C.

NMR ¹H (DMSO, 400 MHz, δ): 2.16 (m, 2H, ═CH—CH₂); 3.59 (m, 2H, CH₂—N);3.98 (m, 2H, ═CH—CH₂—N); 5.80 (m, 2H, CH═CH); 7.52 (m, 4H, Ph); 7.38 (s,1H, thiophene); 8.16 (m, 2H, thiophene); 8.78 (wide s, 1H, NH⁺); 8.81(s, 1H, CONH); 9.73 (wide s, 1H, NH⁺); 11.41 (wide s, 1H, NH⁺).

IR: ν_(C═O) (urea): 1637 cm⁻¹; ν_(C═N) (amidine): 1583 cm⁻¹.

Example 48

N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidineCarboxamide Fumarate (48)

48.1 2-(R.S)-(4-nitrophenyl)-4-(R)-thiazolidine Carboxylic Acid

3 g (17.08 mmoles) of L-Cysteine hydrochloride and 2.18 g (22.2 mmoles)of sodium acetate are dissolved in 75 ml of water. The solution isagitated vigorously during the addition. by portions, of 3.10 g (20.5mmoles) of 4-nitrobenzaldehyde in solution in 80 ml of 95% ethanol. Awhite precipitate rapidly appears in this pale yellow solution whichforms abundantly. Agitation is maintained for one hour, the reactionmixture is then cooled down to 0° C. and filtered. The precipitate issuccessively rinsed with 200 ml of water, 100 ml of cold ethanol and 100ml of ethyl ether. After drying. a white powder is obtained with a yieldof 87%. Melting point: 120-121° C.

NMR ¹H (Acetone D6, 100 MHz, δ): 3.50 (m, 2H, CH₂—S); 4.25 (m, 1H,CH—CO); 4.75 (hump, 2H, CO₂H+NH); 5.86 (s, 1H, N—CH—S); 8.20 (m, 4H,Ph).

48.23-[(1,1-dimethylethoxy)carbonyl]-2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidineCarboxylic Acid

The experimental protocol used is the same as that described forintermediate 47.1, 2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidine carboxylicacid replacing 4-(t-butoxycarbonylamino)-benzeneacetic acid. A paleyellow powder is obtained with a yield of 59%. Melting point: 145-146°C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.35 (m, 9H, tBu); 3.40 (m, 2H, CH₂—S); 4.95(m, 1H, CH—CO); 6.10 (m, 1H, N—CH—S); 8.00 (m, 4H, Ph); 10.00 (wide s,1H, CO₂H).

48.33-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidineCarboxamide

The experimental protocol used is the same as that described forintermediate 46.3,3-[(1,1-dimethylethoxy)carbonyl]-2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidinecarboxylic acid replacing2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-4-(4-nitrophenoxy)-proline.A white powder is obtained with a yield of 41%. Melting point: 226-227°C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (m, 27H, 3×tBu); 3.52 (m, 2H, CH₂—S);5.00 (m, 1H, CH—CO); 5.15 (s, 1H, OH); 6.10 (wide s, 1H, N—CH—S); 7.30(s, 2H, Ph-OH); 7.92 (m, 4H, Ph-NO₂); 8.60 (wide s, 1H, CONH).

48.43-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-(4-aminophenyl)-4-(R)-thiazolidineCarboxamide

The experimental protocol used is the same as that described forintermediate 44.2,3-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidinecarboxamide replacing2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone.The expected product is obtained in the form of a pale yellow powderwith a yield of 21%. Melting point: 196-198° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.40 (m, 27H, 3×tBu); 3.50 (m, 4H,CH₂—S+NH₂); 5.00 (m, 1H, CH—CO); 5.10 (s, 1H, OH); 6.01 (wide s, 1H,N—CH—S); 6.98 (m, 4H, Ph-NH₂); 7.25 (s, 2H, Ph-OH); 8.50 (wide s, 1H,CONH).

48.5N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidineCarboxamide Fumarate (48)

The experimental protocol used is the same as that described forintermediate 46.5, intermediate 48.4 replacing2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-(4-aminophenoxy)-prolinamide.Compound 48.5 obtained in the form of the free base is then salified inthe presence of fumaric acid under reflux of ethanol for 30 minutes. Ayellow powder is obtained with an overall yield of 30%. Melting point:201-204° C.

NMR ¹H (DMSO, 400 MHz, δ): 1.37 (s, 18H, 2×tBu); 3.17 (m, 2H, CH₂—S);3.29 (wide s, 1H, NH thiazolidine); 3.91 (m, _H, CH—CO); 4.31 (m, _H,CH—CO); 5.59 (s, _H, N—CH—S); 5.67 (s, _H, N—CH—S); 6.61 (s, 2H, fum,);6.74 (m, 2H, NH₂ amidine); 7.11 (m, 1H, thiophene); 7.19 (m, 4H, Ph-N);7.42 (s, 2H, Ph-OH); 7.62 (m, 1H, thiophene); 7.73 (wide s, 1H,thiophene); 9.69 (s, _H, CONH); 9.95 (s, _H, CONH).

IR: ν_(OH): 3625-3421 cm⁻¹; _(C═O) (amide): 1652 cm⁻¹; ν_(C═N)(amidine): 1604 cm⁻¹.

Example 49

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamideHydroiodide (49)

49.1 4-nitrobenzene-carbothioamide

6.06 g (15 mmol) of Lawesson reagent is added to a solution of 4.15 g(25 mmol) of 4-nitrobenzamide in 100 ml of 1,4-dioxan. The reactionmixture is heated under reflux for two hours. After the solution hasreturned to ambient temperature, it is poured into 150 ml of water andextracted with 5 times 100 ml of ethyl acetate. The organic solution isdried over magnesium sulphate, filtered and concentrated under vacuum inorder to produce a yellow oil which is purified on a silica gel column(eluant: heptane/ethyl acetate 1/1). The pure fractions are collectedand concentrated under vacuum. 3.26 g of a yellow powder is obtainedwith a yield of 72%. Melting point: 165-167° C.

49.2 Ethyl 2-(4-nitrophenyl)-4-thiazolecarboxylate

3.26 g (17.9 mmol) of intermediate 49.1 and 2.26 ml (18 mmol) of ethylbromopyruvate are introduced successively into a flask containing 100 mlof DMF. After agitating the reaction mixture at 23° C., for 1 hour, thesolution is concentrated under vacuum. The evaporation residue isdissolved in 150 ml of dichloromethane and washed successively with 100ml of water and 100 ml of salt water. After drying over magnesiumsulphate and filtration, the organic solution is concentrated undervacuum. The powder obtained is then agitated in the presence of 100 mlof a (3/1) mixture of toluene and ethanol, filtered and rinsed with 25ml of the same mixture of solvents. 3.2 g (60%) of a beige powder isobtained. Melting point: 156-158° C.

49.3 2-(4-nitrophenyl)-4-thiazolecarboxylic Acid

A solution of 0.82 g (14.5 mmol) of KOH in 5 ml of water is addeddropwise at 23° C. to a solution of intermediate 49.2 (2.15 g, 7.25mmol) in 100 ml of acetone. After agitation overnight, the precipitateformed is filtered off and rinsed with 10 ml of acetone. Thisprecipitate is taken up in a mixture of 100 ml of ethyl acetate and 100ml of a 1M solution of HCl. After decantation. the aqueous phase isreextracted with 25 ml of ethyl acetate. The organic phases arecollected and washed successively with 25 ml of water and 50 ml of saltwater. The organic solution is dried over sodium sulphate, filtered andconcentrated under vacuum in order to produce a yellow powder with ayield of 93%. Melting point: 250-252° C.

49.4N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-(4-nitrophenyl)-4-thiazolecarboxamide

The experimental protocol used is the same as that described forintermediate 46.3, intermediate 49.3 replacing intermediate 46.2. Theexpected compound is obtained in the form of a yellow powder with ayield of 51%. Melting point: 262-264° C.

NMR ¹H (acetone d6, 100 MHz, δ): 1.60 (s, 18H, 2 tBu), 6.12 (s, 1H, OH),8.21 (m, 2H, arom. H), 8.50 (s, 4H, arom. H), 8.60 (s, 1H, thiazole),9.93 (wide s, 1H, CO—NH).

49.5N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-(4-aminophenyl)-4-thiazolecarboxamide

3.59 g (16 mmol) of SnCl₂.2H₂O is introduced into a solution ofintermediate 49.4 (1.50 g, 3.18 mmol) in 50 ml of an ethylacetate/ethanol/acetone mixture (2/1/2). The reaction mixture is heatedunder reflux for 5 hours and finally after cooling down, concentrationto one half is carried out under vacuum. The evaporation residue is thenpoured into 50 ml of cold water, the precipitate which forms is dilutedwith 100 ml of ethyl acetate and 25 ml of a saturated solution ofNaHCO₃. The cloudy mixture is filtered on celite and the filtrate isdecanted. The organic phase is washed successively with 50 ml of waterand 50 ml of salt water. After drying over magnesium suphate andfiltration, the organic solution is concentrated under vacuum in orderto produce a bright yellow powder which is purified by washing with anEt₂O/heptane mixture (90/10). The expected compound is obtained in theform of a pale yellow powder with a yield of 55%. Melting point:267-268° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.49 (s, 18H, 2 tBu), 4.00 (wide s, 2H,NH₂), 5.11 (s, 1H, OH), 6.72 (m, 2H, arom. H), 7.60 (s, 2H, arom. H),7.81 (m, 2H, arom. H), 8.05 (s, 1H, thiazole), 9.10 (wide s, 1H, CO—NH).

49.6N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamideHydroiodide (49)

The experimental protocol used is the same as that described forintermediate 33.3, intermediate 49.5 replacing intermediate 33.2. Ayellow powder is obtained with a yield of 27%. Melting point: 270-272°C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 6.89 (s, 1H, OH),7.41 (m, 1H, arom. H), 7.63 (m, 4H, arom. H), 8.11 (m, 1H, arom. H),8.20 (m, 1H, arom. H), 8.36 (m, 2H, arom. H), 8.48 (s, 1H, arom. H),9.19 (wide s, 1H, NH⁺), 9.90 (wide s, 1H, NH⁺), 10.02 (s, 1H, CO—NH),11.50 (s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1660 cm⁻¹; ν_(C═N) (amidine): 1646 cm⁻¹.

Example 50

N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamideDihydrochloride (50)

50.1 1-(1,1-dimethylethyl) and 2-methyl4-(S)-(4-nitrophenoxy)-1,2-(R)-pyrrolidinedicarboxylate

4.38 g (31.5 mmoles) of 4-nitrophenol in solution in 40 ml of anhydrousN-methyl-2-pyrrolidinone is added dropwise to a suspension of 1.26 g(31.5 mmoles) of NaH at 60% in 60 ml of anhydrousN-methyl-2-pyrrolidinone in a three-necked flask cooled down to 0° C.under an inert atmosphere. The reaction is accompanied by a significantrelease of hydrogen. After agitation for one hour at 0° C. 6 g (15mmoles) of 1-(1,1-dimethylethyl) and 2-methyl4-(R)-{[(4-methylphenyl)sulphonyl]oxy}-1,2-(R)-pyrrolidinedicarboxylateis added in one go, agitation is maintained for another 15 hours at 23°C. and the reaction is completed by 5 hours of reflux. After thereaction mixture is returned to 23° C., it is diluted with 150 ml ofethyl acetate and 100 ml of a 1M solution of soda. After decantation,the aquoeus phase is reextracted twice with 50 ml of ethyl acetate. Theorganic phases are collecteed and washed successively with 1N soda(until the excess of 4-nitrophenol of the organic phase disappears),with water until neutrality is achieved and finally with 100 ml of saltwater. After drying over magnesium sulphate and filtration, the organicsolution is concentrated under vacuum in order to produce an oily brownresidue which is purified on a silica column (eluant: heptane/ethylacetate: 8/2). The pure fractions are collected and concentrated undervacuum in order to produce a pale yellow oil with a yield of 83%.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.41 (s, 9H, tBu), 2.40 (m, 2H, CH₂), 3.80(s, 5H, CH₃+CH₂), 4.50 (m, 1H, CH—N), 5.03 (m, 1H, CH—O), 6.95 (m, 2H,arom. H), 8.22 (m, 2H, arom. H).

50.2 1,1-dimethylethyl2-(R)-carboxy-4-(S)-(4-nitrophenoxy)-1-pyrrolidinecarboxylate

A solution of 2.14 g (38 mmoles) of KOH in 15 ml of water is addeddropwise at 0° C. to a solution of 7 g (19 mmoles) of intermediate 50.1in 100 ml of methanol. The reaction mixture is agitated at 23° C. for 15hours and finally concentrated to one half under vacuum. After dilutionwith 50 ml of ethyl acetate and 50 ml of 1N soda, the mixture isdecanted. The organic phase is eliminated and the aquoeus phase isacidified cold with 1M HCl, the product is then extracted with 100 ml ofethyl acetate. The organic solution is then washed with 50 ml of waterand 50 ml of salt water. After drying over magnesium sulphate andfiltration, the solution is concentrated under vacuum. A pale yellow oilis obtained with a yield of 66%.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 2.52 (m, 2H, CH₂), 3.80(m, 2H, CH₂), 4.48 (m, 1H, CH—N), 5.03 (m, 1H, CH—O), 5.92 (wide s,CO₂H), 6.92 (m, 2H, arom. H), 8.20 (m, 2H, arom. H).

50.3 1,1-dimethylethyl2-(R)-{[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino]carbonyl}-4-(S)-(4-nitrophenoxy)-pyrrolidine-1-carboxylate

The experimental protocol used is the same as that described forintermediate 46.3, intermediate 50.2 replacing intermediate 46.2. Abeige powder is obtained with a yield of 43%. Melting point: 140-142° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 18H, 2 tBu), 1.50 (s, 9H, tBu),2.30 (m, 1H, 1/2 CH₂), 2.95 (m, 1H, 1/2 CH₂), 3.75 (m, 2H, CH₂), 4.65(m, 1H, CH—N), 5.10 (m, 2H, CH—O+OH), 6.98 (m, 2H, arom. H), 7.31 (s,2H, arom. H), 8.22 (m, 2H, arom. H), 9.10 (wide s, 1H, CO—NH).

50.4 1,1-dimethylethyl2-(R)-{[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino]carbonyl}-4-(S)-(4-aminophenoxy)-pyrrolidine-1-carboxylate

The experimental protocol used is the same as that described forintermediate 46.4, intermediate 50.3 replacing intermediate 46.3. Afterpurification on a silica column (eluant: heptane/ethyl acetate: 1/1) andconcentration of the pure fractions, the expected compound is obtainedin the form of a beige powder with a yield of 70%. Melting point:104-106° C. NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 18H, 2 tBu), 1.50 (s,9H, tBu), 1.60 (s, 2H, NH₂), 2.10 (m, 1H, 1/2 CH₂), 2.80 (m, 1H, 1/2CH₂), 3.60 (m, 2H, CH₂), 4.60 (m, 1H, CH—N), 4.85 (m, 1H, CH—O), 5.04(s, 1H, OH), 6.70 (m, 4H, arom. H), 7.34 (s, 2H, arom. H), 9.10 (wide s,1H, CO—NH).

50.5N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamideDihydrochloride (50)

The experimental protocol used is the same as that described forintermediate 34.4, intermediate 50.4 replacing3-(4-aminobenzyl)-thiazolidine. The free base, obtained in the form of alight yellow powder, is directly deprotected in the presence of 10equivalents of a 4M solution of anhydrous HCl in 1,4-dioxan. Afteragitation for 15 hours, the precipitate formed is filtered, the crystalsare washed with acetone followed by ethyl ether. The expected product isobtained in the form of a pale yellow powder with a yield of 53%.Melting point: 245-247° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.36 (s, 18H, 2 tBu), 2.29 (m, 1H, 1/2CH₂), 2.71 (m, 1H, 1/2 CH₂), 3.42 (m, 1H, 1/2 CH₂), 3.77 (m, 1H, 1/2CH₂), 4.57 (m, 1H, CH—N), 5.26 (m, 1H, CH—O), 6.93 (s, 1H, OH), 7.17 (m,2H, arom. H), 7.37 (m, 1H, arom. H), 7.42 (m, 2H, arom. H), 7.48 (s, 2H,arom. H), 8.17 (m, 2H, arom. H), 8.81 (wide s, 1H, NH⁺), 9.03(wide s,1H, NH⁺), 9.78 (wide s, 1H, NH⁺), 10.70 (s, 1H, CO—NH), 10.84 (wide s,1H, NH⁺), 11.50 (wide s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1681 cm⁻¹; ν_(C═N) (amidine): 1652 cm⁻¹.

Example 51

Methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylateHydrochloride (51)

51.1 1-(1,1-dimethylethyl) and 2-methyl4-(S)-(4-nitrophenoxy)-1,2-(S)-pyrrolidinedicarboxylate

The experimental protocol used is the same as that described forintermediate 50.1, the 1-(1,1-dimethylethyl) and 2-methyl4-(S)-{[(4-methylphenyl)sulphonyl]oxy}-1,2-(R)-pyrrolidinedicarboxylatederivatives being used instead of the 1-(1,1-dimethylethyl) and 2-methyl4-(R)-{[(4-methylphenyl)sulphonyl]oxy}-1,2-(R)-pyrrolidinedicarboxylatederivatives. The expected product is obtained in the form of a whitepowder with a yield of 63%. Melting point: 155-157° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.37 (2 s, 9H, tBu), 2.22 (m, 1H, 1/2CH₂), 2.62 (m, 1H, 1/2 CH₂), 3.45 (m, 1H, 1/2 CH₂), 3.62 (2 s, 3H,OCH₃), 3.78 (m, 1H, 1/2 CH₂), 4.42 (m, 1H, CH—N), 5.20 (m, 1H, CH—O),7.07 (m, 2H, arom. H), 8.20 (m, 2H, arom. H).

51.2 Methyl 4-(S)-(4-nitrophenoxy)-pyrrolidine-2-(S)-carboxylate

10 ml (94 mmol) of trifluoroacetic acetic diluted with 10 ml ofdichloromethane is added at 0° C. to a a solution of 3.45 g (9.4 mmol)of intermediate 51.1 in 15 ml of dichloromethane. The reaction mixtureis then agitated for 2 hours at 23° C. and finally it is concentratedunder vacuum. The evaporation residue is diluted with 100 ml ofdichloromethane and the organic solution is washed successively 3 timeswith 20 ml of a saturated solution of Na₂CO₃, twice with 20 ml of waterand finally with 20 ml of salt water. After drying over magnesiumsulphate and filtration, the organic solution is concentrated undervacuum in order to produce a pale yellow oil with a yield of 78%.

51.3 Methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-(4-nitrophenoxy)-pyrrolidine-2-(S)-carboxylate

1.3 g (8.06 mmol) of 1,1′-carbonyldiimidazole is added to a solution of1.83 g (7.33 mmol) of Trolox in 20 ml of dry THF. After agitation forone hour at 23° C., a solution of 1.95 g (7.33 mmoles) of intermediate51.2 diluted in 10 ml of dry THF is added dropwise. The reaction mixtureis agitated at 23° C. for 15 hours and finally concentrated to drynessunder vacuum. The residue is diluted with 100 ml of ethyl acetate andthe organic solution is washed twice with 50 ml of water and 50 ml ofsalt water. After drying over magnesium sulphate and filtration, theorganic solution is concentrated under vacuum. The evaporation residueis purified on a silica gel column (eluant: heptane/ethyl acetate: 6/4).The pure fractions are collected and evaporated under vacuum in order toproduce a yellow powder with a yield of 61%. Melting point: 103-105° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.55-2.50 (m, 16H, Trolox), 2.63 (m, 2H,CH₂), 3.60-3.71 (2 s, 3H, OCH₃), 3.85 (m, 2H, CH₂), 4.70-4.88 (2 m, 1H,CH—N), 5.02 (m, 1H, CH—O), 6.82 (m, 2H, arom. H), 8.20 (m, 2H, arom. H).

51.4 Methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-(4-aminophenoxy)-pyrrolidine-2-(S)-carboxylate

The protocol used is the same as that described for intermediate 46.4,intermediate 51.3 replacing intermediate 46.3. The expected product isobtained in the form of a white powder with a yield of 95%. Meltingpoint: 110-112° C.

51.5 Methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-[4-[(imino(2-thienyl)methyl)amino]phenoxy]-pyrrolidine-2-(S)-carboxylateHydrochloride (51)

The protocol used is the same as that described for intermediate 34.4,intermediate 51.4 replacing intermediate 34.3. The condensation reactionis carried out in 2-propanol only. After salification, the expectedproduct is obtained in the form of a pale yellow powder with a yield of75%. Melting point: 203-206° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.55-2.50 (m, 16H, Trolox), 2.45 (m, 2H,CH₂), 3.45-3.60 (2 s, 3H, OCH₃), 3.70 (m, 2H, CH₂), 4.51 (m, 1H, CH—N),5.02 (m, 1H, CH—O), 7.00 (m, 2H, arom. H), 7.39 (m, 3H, arom. H), 8.16(m, 2H, arom. H), 8.80 (wide s, 1H, NH⁺), 9.75 (wide s, 1H, NH⁺), 11.36(wide s, 1H, NH⁺). IR: ν_(C═O) (amide): 1650 cm⁻¹; ν_(C═N) (amidine):1611 cm⁻¹.

Example 52

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidineHydrochloride (52)

52.11,1-dimethylethyl:3-(R)-{[(4-methylphenyl)sulphonyl]oxy}-1-pyrrolidinecarboxylate

21.6 g (114 mmol) of p-toluenesulphonyl chloride is added to a solutionof 10 g (57 mmol) of (R)-N-Boc-3-pyrrolidinol (prepared in a standardfashion starting from commercial (R)-3-pyrrolidinol) and 13.7 ml (171mmoles) of pyridine in 150 ml of dichloromethane). After agitation for24 hours at 23° C., the reaction mixture is washed with 3 times 50 ml ofa 1M solution of HCl. After decantation, the organic phase is washedwith 50 ml of water followed by 50 ml of salt water and finally driedover magnesium sulphate, filtred and concentrated under vacuum. Theevaporation residue is purified rapidly on a silica column (eluant:heptane/ethyl acetate: 8/2) in order to produce a pale yellow oil with ayield of 67%.

52.2 1,1-dimethylethyl 3-(S)-(4-nitrophenoxy)-1-pyrrolidine-carboxylate

The experimental protocol used is the same as that described forintermediate 50.1, intermediate 52.1 replacing the 1-(1,1-dimethylethyl)2-methyl4-(R)-{[(4-methylphenyl)sulphonyl]oxy}-1,2-(R)-pyrrolidinedicarboxylatederivative. The expected product is obtained in the form of a lightyellow powder with a yield of 77%. Melting point: 112-114° C.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 2.20 (m, 2H, CH₂), 3.60(m, 4H, CH₂—CH₂), 5.00 (m, 1H, CH—O), 6.94 (m, 2H, arom. H), 8.20 (m,2H, arom. H).

52.3 3-(S)-(4-nitrophenoxy)pyrrolidine

The experimental protocol used is the same as that described forintermediate 51.2, intermediate 52.2 replacing intermediate 51.1. Abrown oil is obtained with a quantitative yield.

52.41-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-(4-nitrophenoxy)pyrrolidine

The experimental protocol used is the same as that described forintermediate 51.3, intermediate 52.3 replacing intermediate 51.2. Theexpected product is obtained after chromatography on a silica column(eluant: heptane/ethyl acetate: 7/3). The pure fractions, afterevaporation, produce a beige powder with a yield of 23%. Melting point:176-178° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.52-2.60 (m, 16H, Trolox), 2.62 (m, 2H,CH₂), 3.50-4.40 (m, 4H, CH₂—CH₂), 4.80 (m, 1H, CH—O), 6.89 (m, 2H, arom.H), 8.20 (m, 2H, arom. H).

52.51-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-(4-aminophenoxy)pyrrolidine

The experimental protocol used is the same as that described forintermediate 46.4, intermediate 52.4 replacing intermediate 46.3. Awhite powder is obtained with a yield of 78%. Melting point: 98-100° C.

52.61-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}pyrrolidineHydrochloride (52)

The protocol used is the same as that described for intermediate 34.4,intermediate 52.5 replacing intermediate 34.3. The condensation reactionis carried out in 2-propanol only. After salification, the expectedproduct is obtained in the form of a pale yellow powder with a yield of85%. Melting point: 195-197° C.

NMR ¹H (pyridine d5, 400 MHz, δ): 1.52-2.48 (m, 16H, Trolox), 2.60-3.05(m, 2H, CH₂), 3.58-4.42 (m, 4H, CH₂—CH₂), 4.59-4.90 (m, 1H, CH—O), 6.65(m, 1H, arom. H), 6.89 (m, 2H, arom. H), 7.01 (m, 1H, arom. H), 7.15 (m,1H, arom. H), 7.30 (m, 1H, NH⁺), 7.41 (m, 1H, NH⁺), 7.74 (m, 2H, arom.H), 8.95 (m, 1H, NH⁺).

IR: ν_(C═O) (amide): 1650 cm⁻¹; ν_(C═N) (amidine): 1610 cm⁻¹

Example 53

3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)-carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine(53)

53.13-{[(1,1-dimethylethoxy)carbonyl]amino}-1-(4-nitrophenyl)pyrrolidine

The experimental protocol used is the same as that described forintermediate 33.1, 3-(tert-butoxycarbonylamino)pyrrolidine replacingimidazole.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 2.20 (m, 2H, CH₂), 3.50(m, 4H, 2×CH₂—N), 4.35 (m, 1H, CH—N), 4.75 (m, 1H, NH), 6.45 (m, 2H,arom. H), 8.10 (m, 2H, arom. H).

53.2 3-amino-1-(4-nitrophenyl)pyrrolidine

The experimental protocol used is the same as that described forintermediate 51.2, intermediate 53.1 replacing intermediate 51.1.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.50 (wide s, 2H, NH₂), 2.10 (m, 2H, CH₂),3.10 (m, 1H, CH), 3.50 (m, 4H, 2×CH₂), 6.40 (m, 2H, arom. H), 8.10 (m,2H, arom. H).

53.33-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-(4-nitrophenyl)pyrrolidine

The experimental protocol used is the same as that described forintermediate 51.3, intermediate 53.2 replacing intermediate 51.2. Ayellow solid is obtained which is used directly in the following stagewithout further purification.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.50-2.20 (m, 18H, Trolox+CH₂), 3.45 (m, 4H,2×CH₂), 4.40 (m, 1H, CH), 4.50 (wide s, 1H, NH), 8.15 (m, 2H, arom. H),8.35 (m, 2H, arom. H).

53.43-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-(4-aminophenyl)pyrrolidine

The experimental protocol used is the same as that described forintermediate 46.4, intermediate 53.3 replacing intermediate 46.3.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.50-2.50 (m, 18H, Trolox+CH₂), 3.15 (m, 4H,2×CH₂), 4.50 (m, 2H, CH+NH), 6.40 (m, 4H, arom. H).

53.53-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine(53)

The experimental protocol used is the same as that described forintermediate 34.4, intermediate 53.4 replacing intermediate 34.3. Theexpected product is obtained in the form of a yellow powder (free base)with a yield of 81%. Melting point: 135-138° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.39-2.50 (m, 18H, Trolox+CH₂), 2.85-3.43(m, 4H, 2×CH₂), 4.37 (m, 1H, CH), 6.23 (wide s, 2H, NH₂), 6.46 (m, 2H,arom. H), 6.73 (m, 2H, arom. H), 7.07 (m, 1H, arom. H), 7.17 (d. 1/2H,1/2 CONH. J=7.6 Hz), 7.34 (d. 1/2H, 1/2 CONH. J=7.6 Hz), 7.56 (m, 1H,arom. H), 7.68 (m, 1H, arom. H).

IR: ν_(C═O) (amide): 1657 cm⁻¹; ν_(C═N) (amidine): 1626 cm⁻¹.

Example 54

4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamineHydrochloride (54)

54.1 {[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]carbonyl}methylN-methyl-N-[(phenylmethoxy)carbonyl]glycinate

This intermediate is obtained in a standard fashion starting fromCbz-Sarcosine and1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-bromo-ethanone in thepresence of caesium carbonate in DMF.

NMR ¹H (CDCl₃, 100 MHz, d): 1.46 (s, 18H, 2 tBu), 3.00 (s, 3H, N—CH₃),4.20 (m, 2H, O—CH₂-Ph), 5.10-5.40 (m, 4H, CH₂ —N(CH₃)+CO—CH₂ —O—CO),5.80 (s, 1H, OH), 7.30 (m, 5H, arom. H), 7.70 (s, 2H, arom. H).

54.24-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-[(phenylmethoxy)-carbonyl]-1H-imidazole-2-methanamine

This intermediate is obtained, starting from intermediate 54.1, usingthe same experimental protocol as that described in Tetrahedron Lett,.1993. 34. 1901. A pale green powder is obtained with a yield of 81%.Melting point: 200-207° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.00 (s, 3H, N—CH₃),4.5 (m, 2H, O—CH₂-Ph), 5.10 (s, 2H, CH₂ —N—COO), 5.20 (s, 1H, OH), 7.00(s, 1H, imidazole), 7.20-7.50 (m, 7H, arom. H), 9.90 (s, 1H, NH).

54.34-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyll-N-methyl-N-[(phenylmethoxy)-carbonyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-methanamine

7.1 g (51.2 mmol) of potassium carbonate is added by portions to amixture of 9.96 ml (56.3 mmol) of 2-(trimethylsilyl)ethoxymethylchloride and 23 g (51.2 ml) of intermediate 54.2 in 200 ml of DMF. Whenthe addition is finished, the reaction mixture is agitated for 3 hoursat 50° C. The solvent is then eliminated under vacuum and the residue isdiluted with 200 ml of ethyl acetate. The organic solution is washedtwice with 100 ml of salt water, dried over magnesium sulphate, filteredand concentrated under vacuum. The evaporation residue is purified on asilica gel column (eluant heptane/ethyl acetate: 1/1). The purefractions are evaporated in order to produce a green oil with a yield of53%.

NMR ¹H (CDCl₃, 400 MHz, δ): 0.0 (s, 9H, Si(CH₃)₃), 0.9 (m, 2H, CH₂—Si),1.50 (s, 18H, 2 tBu), 3.00 (s, 3H, N—CH₃), 3.30-3.50 (m, 2H, O—CH₂—CH₂—Si), 4.70 (s, 2H, CH₂ —N—COO), 5.10 (s, 2H, O—CH₂-Ph), 5.20 (s, 2H,imidazole-CH₂ -OSEM), 5.30 (s, 1H, OH), 7.20 (s, 1H, imidazole), 7.35(m, 5H, arom. H), 7.60 (s, 2H, arom. H).

54.44-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazole-2-methanamine

The experimental protocol used is the same as that described forintermediate 46.4, intermediate 54.3 replacing intermediate 46.3. Abrown oil is obtained with a yield of 98%.

NMR ¹H (CDCl₃, 100 MHz, δ): 0.0 (s, 9H, Si(CH₃)₃), 0.9 (m, 2H, CH₂—Si),1.50 (s, 18H, 2 tBu), 2.50 (s, 3H, N—CH₃), 3.50 (m, 2H, O—CH₂ —CH₂—Si),4.00 (s, 2H, N—CH₂ —imidazole), 5.20 (s, 1H, OH), 5.40 (s, 2H,imidazole-CH₂ -OSEM), 7.10 (s, 1H, imidazole), 7.50 (s, 2H, arom. H).

54.54-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrobenzoyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-methanamine

A solution of 2.67 g (14.4 mmol) of 4-nitrobenzoic acid chloride in 50ml of dry THF is added dropwise to a solution of 5.34 g (11.9 mmol) ofintermediate 54.4 and 2 ml (14.4 mmol) of triethylamine in 50 ml ofdichloromethane. After agitation for 2 hours at 23° C., the mixture isdiluted with 100 ml of dichloromethane and the organic solution iswashed with twice 100 ml of salt water. After drying over magnesiumsulphate, the organic phase is filtered and concentrated under vacuum inorder to produce a yellow oil which is used as it is in the followingstage.

NMR ¹H (CDCl₃, 400 MHz, δ): 0.0 (s, 9H, Si(CH₃)₃), 0.9 (m, 2H, CH₂—Si),1.50 (s, 18H, 2 tBu), 3.15 (s, 3H, N—CH₃), 3.50 (m, 2H, O—CH₂ —CH₂—Si),4.80 (s, 2H, N—CH₂ -imidazole), 5.20 (s, 2H, imidazole-CH₂ -OSEM), 5.30(s, 1H, OH), 6.90 (m, 2H, arom. H), 7.15 (s, 1H, imidazole), 7.60 (s,2H, arom. H), 8.10 (m, 2H, arom. H).

54.64-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrobenzoyl)-1H-imidazole-2-methanamine

Intermediate 54.5 (7.42 g, 12.5 mmol) is dissolved in 62.4 ml (62.4mmol) of a 1M solution of tetrabutylammonium fluoride in the presence of1.12 g (18.7 mmol) of ethylenediamine. The reaction mixture is heatedunder reflux for 5 hours and finally poured directly into 200 ml of saltwater and diluted with 200 ml of ethyl acetate. The organic phase isdecanted, washed with 100 ml of salt water and finally dried overmagnesium sulphate, filtered and concentrated under vacuum. Theevaporation residue is purified on a silica column (eluant:dichloromethane+5% of ethanol). The expected product is obtained in theform of a red foam with a yield of 37%.

NMR ¹H (CDCl₃, 400 MHz, d): 1.50 (s, 18H, 2 tBu), 3.00 (s, 3H, N—CH₃),4.70 (s, 2H, N—CH₂ -imidazole), 5.20 (s, 1H, OH), 7.10 (s, 1H,imidazole), 7.40-7.60 (m, 4H, arom. H), 8.30 (m, 2H, arom. H), 10.10(wide s, 1H, NH).

54.74-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminobenzoyl)-1H-imidazole-2-methanamine

The experimental protocol used is the same as that described forintermediate 46.4, intermediate 54.6 replacing intermediate 46.3. Anorange solid is obtained with a yield of 52%. Melting point: 129-131° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.10 (s, 3H, N—CH₃),3.90 (s, 2H, N—CH₂ -imidazole), 4.70 (s, 2H, NH₂), 5.20 (s, 1H, OH),6.60 (m, 2H, arom. H), 7.10 (s, 1H, Imidazole), 7.30-7.60 (m, 4H, arom.H), 10.30 (wide s, 1H, NH).

54.84-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl]-N-methyl-1H-imidazole-2-methanamineHydrochloride (54)

The experimental protocol used is the same as that described forintermediate 36.3, intermediate 54.7 replacing intermediate 36.2. Alight beige solid is obtained with a yield of 54%. Melting point:250-260° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.20 (s, 3H, N—CH₃),5.00 (s, 2H, N—CH₂ -imidazole), 7.30 (s, 1H, OH), 7.35 (m, 1H,thiophene), 7.50 (m, 4H, arom. H), 7.70 (s, 2H,a. H), 8.00 (s, 1H,Imidazole), 8.20 (m, 2H, thiophene), 9.20 (s, 1H, NH⁺), 10.00 (s, 1H,NH⁺), 11.8 (s, 1H, NH³⁰ ), 14.8 (s, 1H, NH⁺), 15.2 (s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1635 cm⁻¹; ν_(C═N) (amidine): 1601 cm⁻¹.

Example 55

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamideHydroiodide (55)

55.1 Ethyl 1-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

0.9 g (7.2 mmol) of the methyl ester of pyrrole-2-carboxylic acid(prepared in a standard fashion by the esterification of commercialpyrrole-2-carboxylic acid) diluted with 10 ml of dry DMF is addeddropwise at 0° C., under an inert atmosphere, to a suspension of 0.3 g(7.4 mmol) of NaH at 60% in 15 ml of dry DMF. After agitation for onehour at 23° C., a solution of 1.01 g (7.2 mmol) of 4-fluoronitrobenzenein 10 ml of dry DMF is added dropwise. The reaction mixture is thenheated for 3 hours at 80° C. After the reaction medium has returned to23° C., it is poured into 100 ml of an ice+water mixture and finallydiluted with 200 ml of ethyl acetate. After decantation, the organicphase is washed with 3 times 100 ml of water followed by 100 ml of saltwater. The organic solution is dried over magnesium sulphate, filteredand concentrated under vacuum. The evaporation residue is purified on asilica column (eluant: heptane/ethyl acetate: 9/1). The pure fractionsare collected and evaporated under vacuum in order to produce a paleyellow powder with a yield of 49%.

55.2 1-(4-nitrophenyl)-1H-pyrrole-2-carboxylic Acid

A solution of 0.5 g (7.1 mmol) of KOH in 5 ml of water is added to aflask containing a solution of 0.87 g (3.5 mmol) of intermediate 55.1 in20 ml of THF cooled down to 0° C. The reaction mixture is agitated for24 hours at 55° C. and finally diluted with 100 ml of ethyl acetate.After decantation, the organic phase is eliminated and the aqueous phaseis cooled down using an ice bath before acidification with a solution ofconcentrated HCl. The precipitate formed is then filtered and washedtwice with 20 ml of water. After drying. the expected product isobtained with a yield of 66%.

55.3N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-(4-nitrophenyl)-1H-pyrrole-2-carboxamide

The experimental protocol used is the same as that described forintermediate 46.3, intermediate 55.2 replacing intermediate 46.2. Theexpected compound is obtained in the form of a greenish powder with acrude yield of 25%. The product is used such as it is in the followingstage.

55.4N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-(4-aminophenyl)-1H-pyrrole-2-carboxamide

The experimental protocol used is similar to that described forintermediate 46.4, intermediate 55.3 replacing intermediate 46.3. Thereaction is carried out in a dichloromethane/ethanol mixture (1/1). Awhite powder is obtained with a yield of 61%. Melting point: 218-219° C.

55.5N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamideHydroiodide (55)

The experimental protocol used is similar to that described forintermediate 33.3, intermediate 55.4 replacing intermediate 33.2. A paleyellow powder is obtained with a yield of 73%. Melting point: 271-272°C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.35 (s, 18H, 2 tBu), 6.36 (s, 1H, OH),6.78 (s, 1H, arom. H), 7.01 (s, 1H, arom. H), 7.16 (s, 1H, arom. H),7.45 (m, 7H, arom. H), 8.10 (m, 1H, arom. H), 8.19 (m, 1H, arom. H),9.16 (wide s, 1H, NH⁺), 9.89 (wide s, 2H, CONH+NH⁺), 11.39 (wide s, 1H,NH⁺).

IR: ν_(C═O) (amide): 1633 cm⁻¹; ν_(C═N) (amidine): 1609 cm⁻¹.

Example 56

1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinoneHydroiodide (56)

56.1N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-(2-chloroethyl)urea

0.17 ml (2 mmol) of chloroethylisocyanate is added to a flask containinga solution of 0.5 g (2 mmol) of intermediate 10.2 in 5 ml of DMF. Thereaction mixture is agitated for 2 hours at 23° C. and finally dilutedwith 100 ml of ethyl acetate and 25 ml of water. After decantation, theorganic solution is washed with 25 ml of water, twice with 25 ml of saltwater and finally dried over magnesium sulphate. After filtration andevaporation, the residue is taken up in isopentane in order to finallyproduce the expected product, in the form of a pink solid, with a yieldof 83%. Melting point: 169-171° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.35 (t, 2H, CH₂-NH, J=6.0 Hz), 3.60 (t, 2H, CH₂—Cl, J=6.0 Hz), 6.20 (t, 1H, NH—CH₂,J=5.6 Hz), 6.60 (s, 1H, OH), 7.10 (s, 2H, arom. H), 8.30 (s, 1H, NH-Ph).

56.2 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-imidazolidinone

A solution of 0.22 g (1.93 mmol) of tBuO⁻K⁺ in 2 ml of dry DMF is addedto a solution of 0.56 g (1.93 mmol) of intermediate 56.1 in 10 ml of dryDMF. After agitation for 3 hours at 23° C., the reaction mixture isdiluted with 50 ml of water and 100 ml of ethyl acetate. The organicphase is decanted, washed successively with 50 ml of water and 50 ml ofsalt water, dried over magnesium sulphate, filtered and finallyconcentrated under vacuum. The brown oil thus obtained is taken up inisopropyl ether in order to produce a white powder with a yield of 51%.Melting point: 205-207° C.

NMR ¹H (DMSO d6, 100 MHz, δ): 1.40 (s, 18H, 2 tBu), 4.60 (m, 2H, CH₂),4.90 (m, 2H, CH₂), 4.90 (wide s, 1H, NH), 5.00 (s, 1H, OH), 7.15 (s, 2H,arom. H).

56.31-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[(4-nitrophenyl)carbonyl]-2-imidazolidinone

1.28 g (6.9 mmol) of 4-nitrobenzoic acid chloride is added by portionsto a solution of 1.0 g (3.45 mmol) of intermediate 56.2 in a mixture of20 ml of acetonitrile and 10 ml of THF, followed by 0.71 g (5.15 mmol)of potassium carbonate. After agitation for 3 hours at 23° C., thereaction mixture is diluted with 100 ml of dichloromethane and 50 ml ofsalt water. The organic phase,after decantation. is washed with 50 ml ofsalt water and dried over magnesium sulphate. After filtration andconcentration under vacuum, the evaporation residue taken up inisopropyl ether in order to produce a yellow solid with a yield of 83%after drying. Melting point >260° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.95-4.20 (m, 4H, 2CH₂), 5.20 (s, 1H, OH), 7.20 (s, 2H, arom. H), 7.80 (m, 2H, arom. H),8.25 (m, 2H, arom. H).

56.41-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[(4-aminophenyl)carbonyl]-2-imidazolidinone

The experimental protocol used is similar to that described forintermediate 46.4, intermediate 56.3 replacing intermediate 46.3. Theexpected product is obtained in the form of a white powder with a yieldof 45%. Melting point >260° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.90-4.00 (m, 4H, 2CH₂), 5.15 (s, 1H, OH), 6.60 (m, 2H, arom. H), 7.13 (s, 2H, arom. H),7.60 (m, 2H, arom. H).

56.51-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinoneHydroiodide (56)

The experimental protocol used is identical to that described forintermediate 33.3, intermediate 56.4 replacing intermediate 33.2. Theexpected product is obtained in the form of a light beige solid with ayield of 79%. Melting point: 220-260° C.

NMR ¹H (DMSO d6, 400 MHz, d): 1.30 (s, 18H, 2 tBu), 4.00 (m, 4H, 2 CH₂),6.95 (s, 1H, OH), 7.20 (s, 2H, arom. H), 7.40 (m, 1H thiophene), 7.50(m, 2H, arom. H), 7.70 (m, 2H, arom. H), 8.20 (m, 2H, thiophene), 9.20(wide s, 1H, NH⁺), 9.90 (wide s, 1H, NH⁺), 11.60 (wide s, 1H, NH⁺).

IR: ν_(C═O) (urea): 1735 cm⁻¹; ν_(C═O) (amide): 1649 cm⁻¹; ν_(C═N)(amidine): 1595 cm⁻¹.

Example 57

3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamideHydroiodide (57)

57.1 3,5-bis-(1,1-dimethylethyl)-N,4-dihydroxy-benzene Carboxime

This intermediate is prepared according to an experimental protocoldescribed in J. Med. Chem,. 1997, 40, 50-60, starting from commercial3,5-di-tert-butyl-4-hydroxybenzaldehyde. A red foam is obtained with aquantitative yield.

57.2 3,5-bis-(1,1-dimethylethyl)-N,4-dihydroxy-benzene CarboximidoylChloride

The experimental protocol used is the same as that described inTetrahedron Lett,. 1996, 37 (26), 4455, starting from intermediate 57.1.A beige solid is obtained with a crude yield of 77%. The product is useddirectly in the following stage without additional purification.

57.3 Methyl3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleacetate

The reaction of intermediate 57.2 with the methyl ester of 3-butenoicacid is carried out under the same conditions as those described inTetrahedron Lett. 1996, 37 (26), 4455. The expected compound is obtainedin the form of a brown oil with a yield of 49%.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.60 (dd. 1H, 1/2CH₂—C═N, J=16.0 Hz and J=7.8 Hz), 2.90 (dd. 1H, 1/2 CH₂—C═N, J=16.0 Hzand J=5.8 Hz), 3.10 (dd, 1H, 1/2 CH₂—C═O, J=16.6 Hz and J=6.9 Hz), 3.60(dd. 1H, 1/2 CH₂—C═O, J=16.6 Hz and J=10.2 Hz), 5.10 (m, 1H, CH), 5.50(s, 1H, OH), 7.50 (s, 2H, arom. H).

57.43-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleaceticAcid

This intermediate is obtained by the saponification of intermediate 57.3according to an experimental protocol described in J. Med. Chem. 1997,40, 50-60. A white solid is obtained with a yield of 74%. Melting point:229-231° C.

NMR ¹H (CDCl₃, Hz), 2.90 (dd, 1H, 1/2 CH₂—C═N, J=16.3 Hz and J=6.0 Hz),3.10 (dd. 1H, 1/2 CH₂—C═O, J=16.6 Hz and J=6.9 Hz), 3.50 (dd, 1H, 1/2CH₂—C═O, J=16.6 Hz and J=10.2 Hz), 5.05 (m, 1H, CH), 5.50 (s, 1H, OH),7.45 (s, 2H, arom. H).

57.53-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-(4-nitrophenyl)-5-isoxazoleacetamide

The experimental protocol used is the same as that described in Org.Prep. Proced. Int. (1975), 7. 215 starting from intermediate 57.4 and4-nitroaniline. A white solid is obtained with a yield of 45%. Meltingpoint: 149-151° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.70 (m, 1H, 1/2CH₂—C═N), 2.85 (dd, 1H, 1/2 CH₂—C═N, J=15.1 Hz and J=7.5 Hz), 3.20 (dd,1H, 1/2 CH₂—C═O, J=16.7 Hz and J=7.0 Hz), 3.70 (dd, 1H, 1/2 CH₂—C═O,J=16.7 Hz and J=10.1 Hz), 5.05 (m, 1H, CH), 5.50 (s, 1H, OH), 7.45 (s,2H, arom. H), 7.70 (m, 2H, arom. H), 8.20 (m, 2H, arom. H), 8.50 (s, 1H,NH—CO).

57.63-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-(4-aminophenyl)-5-isoxazoleacetamide

The experimental protocol used is the same as that described forintermediate 49.5, intermediate 57.5 replacing intermediate 49.4. Acolourless oil is obtained with a yield of 80%.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.60 (dd, 1H, 1/2CH₂—C═N, J=15.0 Hz and J=5.7 Hz), 2.80 (dd, 1H, 1/2 CH₂—C═N, J=15.0 Hzand J=6.7 Hz), 3.15 (dd, 1H, 1/2 CH₂—C═O, J=16.7 Hz and J=7.2 Hz), 3.50(dd, 1H, 1/2 CH₂—C═O, J=16.7 Hz and J=10.1 Hz), 3.70 (2H, NH₂), 5.10 (m,1H, CH), 5.60 (s, 1H, OH), 6.60 (m, 2H, arom. H), 7.20 (m, 2H, arom. H),7.50 (s, 2H, arom. H), 8.10 (s, 1H, NH—CO).

57.73-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamideHydroiodide (57)

The experimental protocol used is identical to that described forintermediate 33.3, intermediate 57.6 replacing intermediate 33.2. Theexpected product is obtained in the form of a pale yellow powder with ayield of 72%. Melting point >260° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.70 (m, 2H,CH₂—C═N), 3.20 (dd. 1H, 1/2 CH₂—C═O, J=16.8 Hz and J=6.8 Hz), 3.60 (dd,1H, 1/2 CH₂—C═O, J=16.8 Hz and J=10.2 Hz), 5.00 (m, 1H, CH), 7.35 (m,6H, arom. H+OH), 7.80 (m, 2H, arom. H), 8.20 (m, 2H, thiophene), 8.70(wide s, 1H, NH⁺), 9.70 (wide s, 1H, NH⁺), 10.30 (s, 1H, NH—CO), 11.20(wide s, 1H, NH⁺).

IR: ν_(═O) (amide): 1650 cm⁻¹; ν_(C═N) (amidine): 1603 cm⁻¹.

Example 58

4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamineHydrochloride (58)

58.1 2-{[(1,1-dimethylethoxy)carbonyl]methyl}amino-ethanethioamide

The experimental protocol used is identical to that described forintermediate 49.1, N-Boc sarcosinamide (obtained in a standard fashionstarting from commercial sarcosinamide and BocOBoc) is used as startingproduct in place of 4-nitrobenzamide. A white paste is obtained which isused directly in the following stage.

58.24-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-[(1,1-dimethylethoxy)carbonyl]-N-methyl-2-thiazolemethanamine

The experimental protocol used is the same as that described in J. Org.Chem. (1995), 60, 5638-5642, starting from intermediate 58.1 and1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-bromo-ethanone. A brownoil is obtained.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (m, 27H, 3 tBu), 3.00 (s, 3H, N—CH₃),4.70 (s, 2H, CH₂), 5.30 (s, 1H, OH), 7.25 (s, 1H, thiazole), 7.70 (s,2H, arom. H).

58.34-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine

2.3 ml (29 mmol) of TFA is added dropwise at 0° C. to a solution of 2.5g (5.8 mmol) of intermediate 58.2 and 2 ml (1.6 mmol) of triethylsilanein 50 ml of dichloromethane. After agitation for one hour, the reactionmixture is concentrated under vacuum and the residue is diluted with 100ml of ethyl acetate and 50 ml of a saturated solution of NaHCO₃. Afteragitation and decantation, the organic phase is dried over magnesiumsulphate, filtered and concentrated under vacuum. The residue is takenup in heptane in order to produce a white solid, after drying, with ayield of 73%. Melting point: 136° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.60 (s, 3H, N—CH₃),4.20 (s, 2H, CH₂), 5.30 (s, 1H, OH), 7.20 (s, 1H, thiazole), 7.70 (s,2H, arom. H).

58.44-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrophenyl)-2-thiazolemethanamine

The experimental protocol used is the same as that described forintermediate 33.1, intermediate 58.3 replacing imidazole. A yellow solidis obtained with a yield of 23%. Melting point: 199-201° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.25 (s, 3H, N—CH₃),5.10 (s, 2H, CH₂), 6.95 (m, 2H, arom. H), 7.10 (s, 1H, OH), 7.60 (s, 2H,arom. H), 7.80 (s, 1H, thiazole), 8.05 (m, 2H, arom. H).

58.54-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminophenyl)-2-thiazolemethanamine

The experimental protocol used is the same as that described forintermediate 49.5, intermediate 58.4 replacing intermediate 49.4. Theexpected product is obtained in the form of a beige foam with a yield of71%.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.90 (s, 3H, N—CH₃),4.50 (wide s, 2H, NH₂), 4.60 (s, 2H, CH₂), 6.50 (m, 2H, arom. H), 6.60(m, 2H, arom. H), 7.10 (s, 1H, OH), 7.60 (s, 2H, arom. H), 7.70 (s, 1H,thiazole).

58.64-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamineHydrochloride (58)

The experimental protocol used is the same as that described forintermediate 36.3, intermediate 58.5 replacing intermediate 36.2. Awhite powder is obtained with a yield of 67%. Melting point: 157-160° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.15 (s, 3H, N—CH₃),5.00 (s, 2H, CH₂), 6.95 (m, 2H, arom. H), 7.15 (s, 1H, OH), 7.20 (m, 2H,arom. H), 7.40 (m, 1H, thiophene), 7.65 (s, 2H, arom. H), 7.75 (s, 1H,thiazole), 8.15 (m, 2H, thiophene), 8.70 (wide s, 1H, NH⁺), 9.70 (wides, 1H, NH⁺), 11.30 (wide s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1648 cm⁻¹; ν_(C═N) (amidine): 1611 cm⁻¹.

Example 59

4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamineHydrochloride (59)

59.14-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-methanamine

The experimental protocol used is the same as that described forintermediate 33.1, intermediate 54.4 replacing imidazole. A yellow solidis obtained with a yield of 53%. Melting point: 149-151° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 0.0 (s, 9H, Si(CH₃)₃), 0.9 (t, 2H, CH₂—Si,J=8.4 Hz), 1.50 (s, 18H, 2 tBu), 3.15 (s, 3H, N—CH₃), 3.50 (t, 2H, O—CH₂—CH₂—Si, J=8.4 Hz), 4.80 (s, 2H, N—CH₂ -imidazole), 5.20 (s, 2H,imidazole-CH₂ -OSEM), 5.25 (s, 1H, OH), 6.90 (m, 2H, arom. H), 7.10 (s,1H, imidazole). 7.60 (s, 2H, arom. H), 8.15 (m, 2H, arom. H).

59.24-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrophenyl)-1H-imidazole-2-methanamine

The experimental protocol used is the same as that described forintermediate 54.6, intermediate 59.1 replacing intermediate 54.5. Ayellow solid is obtained with a yield of 44%. Melting point: 209-211° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.20 (s, 3H, N—CH₃),4.70 (s, 2H, CH₂), 6.80-7.10 (m, 3H, arom. H), 7.20-7.60 (m, 3H, arom.H+OH), 8.10 (m, 2H, arom. H), 12.00 (s, 1H, NH).

59.34-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminophenyl)-1H-imidazole-2-methanamine

The experimental protocol used is the same as that described forintermediate 46.4, intermediate 59.2 replacing intermediate 46.3. Abeige foam is obtained with a yield of 67%.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.80 (s, 3H, N—CH₃),4.20 (s, 2H, CH₂), 4.30-4.70 (m, 3H, NH₂+NH imidazole), 5.00 (s, 1H,OH), 6.50 (m, 2H, arom. H), 6.70 (m, 2H, arom. H), 6.80 (s, 1H,imidazole), 7.40 (s, 2H, arom. H).

59.44-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamineHydrochloride (59)

The experimental protocol used is the same as that described forintermediate 36.3, intermediate 59.3 replacing intermediate 36.2. Ayellow powder is obtained with a yield of 86%. Melting point: 195-200°C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.20 (s, 3H, N—CH₃),5.00 (s, 2H, CH₂), 7.00 (m, 2H, arom. H), 7.20 (m, 2H, arom. H), 7.40(m, 2H, thiophene+OH), 7.60 (s, 2H, arom. H), 7.90 (s, 1H, imidazole),8.20 (m, 2H, thiophene), 8.70 (wide s, 1H, NH⁺), 9.70 (wide s, 1H, NH⁺),11.40 (wide s, 1H, NH⁺), 14.60 (wide s, 1H, NH⁺), 15.60 (wide s, 1H,NH⁺).

IR: ν_(C═O) (amide): 1646 cm⁻¹; ν_(C═N) (amidine): 1612 cm⁻¹.

Example 60

3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole(60)

60.13-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleethanol

0.09 g (2.4 mmol) of LiAlH₄ is added in small portions to a solution of0.69 g (2.1 mmol) of intermediate 25.3 in 15 ml of dry THF, cooled downto 0° C. After agitation for one hour at 23° C., the reaction mixture iscooled down using an ice bath and the excess hydride is destroyed by theaddition of water (5 ml). The product is extracted using twice 25 ml ofethyl ether. The organic phase is washed twice with 10 ml of salt water,dried over magnesium sulphate, filtered and concentrated under vacuum.The residue is purified on silica (eluant: heptane/ethyl acetate: 1/1).A white foam is obtained with a yield of 58%.

NMR ¹H (DMSO d6, 100 MHz, δ): 1.40 (s, 18H, 2 tBu), 1.60-1.80 (m, 2H,CH₂ —CH₂—O), 3.05 (m, 1H, 1/2 CH₂ isoxazoline), 3.40 (m, 1H, 1/2 CH₂isoxazoline), 3.50 (m, 2H, CH₂—CH₂ —O), 4.60 (s, 1H, OH), 4.70 (m, 1H,CH isoxazoline), 7.40 (wide s, 3H, arom. H+OH).

60.23-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-[2-(4-nitrophenoxy)ethyl]isoxazole

A mixture composed of 0.37 g (1.58 mmol) of intermediate 60.1, 0.5 ml ofAliquat 336, 0.18 g (1.27 mmol) of 4-fluoronitrobenzene and 0.071 g(1.27 mmol) of KOH in 2 ml of toluene is heated at 80° C. for 2 hours.After the reaction mixture has returned to 23° C., it is divided between50 ml of dichloromethane and 20 ml of water. After decantation, theorganic phase is washed with 20 ml of water followed by 20 ml of saltwater. The organic solution is then dried over magnesium sulphate,filtered and concentrated under vacuum. The evaporation residue ispurified on a silica column (eluant: heptane/ethyl acetate: gradient10/0 up to 0/10). A white powder is obtained with a yield of 60%.Melting point: 151-153° C.

NMR ¹H (CDCl₃, 400 MHz, d): 1.50 (s, 18H, 2 tBu), 2.15 (m, 2H, CH₂—CH₂—O), 3.10 (dd, 1H, 1/2 CH₂ isoxazoline, J=16.3 Hz and J=6.65 Hz),3.50 (dd, 1H, 1/2 CH₂ isoxazoline, J=16.3 Hz and J=10.4 Hz), 4.10-4.30(m, 2H, CH₂—CH₂ —O), 5.00 (m, 1H, CH isoxazoline), 5.50 (s, 1H, OH),6.90 (m, 2H, arom. H), 7.50 (s, 2H, arom. H), 8.20 (m, 2H, arom. H).

60.33-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-[2-(4-aminophenoxy)ethyl]isoxazole

The experimental protocol used is the same as that described forintermediate 49.5, intermediate 60.2 replacing intermediate 49.4. Awhite powder is obtained with a yield of 60%. Melting point: 129-131° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.35 (s, 18H, 2 tBu), 2.00 (m, 2H, CH₂—CH₂—O), 3.15 (dd, 1H, 1/2 CH₂ isoxazoline, J=16.7 Hz and J=7.5 Hz),3.40 (dd, 1H, 1/2 CH₂ isoxazoline, J=16.7 Hz and J=10.5 Hz), 3.90 (m,2H, CH₂—CH₂ —O), 4.60 (s, 2H, NH₂), 4.70 (m, 1H, CH isoxazoline), 6.50(m, 2H, arom. H), 6.70 (m, 2H, arom. H), 7.40 (s, 3H, arom. H+OH).

60.43-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole(60)

The experimental protocol used is the same as that described forintermediate 36.3, intermediate 60.3 replacing intermediate 36.2. Awhite solid is obtained with a yield of 32%. Melting point: 240-245° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.15 (m, 2H, CH₂—CH₂ =13 O), 3.20 (dd, 1H, 1/2 CH₂ isoxazoline, J=16.65 Hz and J=7.35Hz), 3.50 (dd, 1H, 1/2 CH₂ isoxazoline, J=16.65 Hz and J=10.3 Hz), 4.20(wide s, 2H, CH₂—CH₂ —O), 4.90 (m, 1H, CH isoxazoline), 7.20 (m, 2H,arom. H), 7.40 (m, 6H, arom. H+OH), 8.20 (m, 2H, thiophene), 8.80 (wides, 1H, NH⁺), 9.80 (wide s, 1H, NH⁺), 11.40 (wide s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1655 cm⁻¹; ν_(C═N) (amidine): 1618 cm⁻¹.

Example 61

1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (61)

61.1 1-(diphenylmethyl)-3-(4-nitrophenoxy)azetidine

0.5 g (2 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine is added underan argon atmosphere to a suspension of 0.06 g (2.3 mmol) of NaH in 20 mlof dry THF. After agitation for one hour at 23° C., a solution of 0.29 g(2.1 mmol) of 4-fluoronitrobenzene in 5 ml of dry THF is added dropwiseto the reaction mixture. Agitation is maintained for another 2 hours at23° C. and the whole is finally poured into 25 ml of water. The productis extracted twice with 25 ml of ethyl acetate, the organic phase isthen washed twice with 25 ml of salt water, dried over magnesiumsulphate, filtered and concentrated under vacuum. The product ispurified on a silica column (eluant: 12% of ethyl acetate in heptane).The pure fractions are evaporated in order to produce a colourless oilwith a yield of 40%.

NMR ¹H (CDCl₃, 400 MHz, d): 3.20 (m, 2H, azetidine), 4.50 (s, 1H,CH-(Ph)₂), 4.80 (m, 2H, azetidine), 4.90 (m, 1H, CH—O), 6.80 (m, 2H,arom. H), 7.20-7.50 (m, 10H, arom. H), 8.20 (m, 2H, arom. H).

61.2 1-(diphenylmethyl)-3-(4-aminophenoxy)azetidine

The experimental protocol used is the same as that described forintermediate 49.5, intermediate 61.1 replacing intermediate 49.4. Acolourless oil is obtained with a yield of 75%.

NMR ¹H (CDCl₃, 400 MHz, δ): 3.10 (m, 2H, azetidine), 3.40 (wide s, 2H,NH₂), 4.40 (s, 1H, CH-(Ph)₂), 4.70 (m, 2H, azetidine), 4.75 (m, 1H,CH—O), 6.60 (s, 4H, arom. H), 7.10-7.40 (m, 10H, arom. H).

61.31-(diphenylmethyl)-3-{4-[(1,1-dimethylethoxy)carbonyl]aminophenoxy}azetidine

Protection of the amine is carried out in a standard fashion withBocOBoc in the presence of triethylamine in dichloromethane. A whitesolid is obtained with a yield of 77%. Melting point: 149-151° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 9H, tBu), 2.90 (wide s, 2H,azetidine), 3.60 (wide s, 2H, azetidine), 4.50 (s, 1H, CH-(Ph)₂), 4.70(m, 1H, CH—O), 6.70 (m, 2H, arom. H), 7.10-7.60 (m, 12H, \rom. H), 9.10(s, 1H, NH).

61.4 3-{4-[(1,1-dimethylethoxy)carbonyl]aminophenoxy}azetidine

The experimental protocol used is the same as that described forintermediate 46.4 except for the hydrogenation catalyst which isreplaced by Pd(OH)₂. A white solid is obtained with a yield of 78%.Melting point 184-186° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 9H, tBu), 3.50 (m, 2H,azetidine), 3.70 (m, 2H, azetidine), 4.90 (m, 1H, CH—O), 6.70 (m, 2H,arom. H), 7.30 (m, 2H, arom. H), 9.10 (s, 1H, NH).

61.51-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}carbonyl}-3-{4-[(1,1-dimethylethoxy)carbonyl]aminophenoxy}azetidine

A solution of 0.6 g (2.7 mmol) of intermediate 42.2 in 10 ml ofdichloromethane is added dropwise, over one hour, to a solution of 0.27g (0.9 mmol) of triphosgene in 6 ml of dichloromethane. After agitationfor 5 minutes at 23° C., a solution of 0.72 g (2.7 mmol) of intermediate61.4 and 0.52 ml (3 mmol) of diisopropylethylamine in 6 ml ofdichloromethane is added in one go. The reaction mixture is agitated for2 hours at 23° C. and finally evaporated to dryness under vacuum. Theresidue is diluted in 50 ml of ethyl acetate and this organic solutionis washed twice with 25 ml of water followed by 25 ml of salt water.After drying over magnesium sulphate and filtration, the organicsolution is concentrated under vacuum. The residue is purified on asilica column (eluant: heptane/ethyl acetate: 7/3). A white solid isobtained with a yield of 61%. Melting point: 224-226° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.35 (s, 18H, 2 tBu), 1.45 (s, 9H, tBu),3.80 (m, 2H, azetidine), 4.30 (m, 2H, azetidine), 4.90 (m, 1H, CH—O),6.60 (s, 1H, OH), 6.70 (m, 2H, arom. H), 7.20 (s, 2H, arom. H), 7.35 (m,2H, arom. H), 8.20 (s, 1H, NH urea), 9.10 (s, 1H, NH).

61.61-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}carbonyl}-3-(4-aminophenoxy)azetidine

The experimental protocol used is the same as that described forintermediate 58.3, intermediate 61.5 replacing intermediate 58.2. Awhite solid is obtained with a yield of 93%. Melting point: 225-227° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.80 (m, 2H,azetidine), 4.30 (m, 2H, azetidine), 4.70 (wide s, 2H, NH₂), 4.85 (m,1H, CH—O), 6.40-6.70 (m, 5H, arom. H+OH), 7.25 (s, 2H, arom. H), 8.20(s, 1H, NH urea).

61.71-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (61)

The experimental protocol used is the same as that described forintermediate 36.3, intermediate 61.6 replacing intermediate 36.2. Awhite solid is obtained with a yield of 16%. Melting point: 235-240° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.90 (m, 2H,azetidine), 4.40 (m, 2H, azetidine), 5.10 (m, 1H, CH—O), 6.60 (s, 1H,OH), 6.90-7.50 (m, 7H, arom. H), 8.20 (m, 2H, thiophene), 8.30 (s, 1H,NH urea), 8.80 (s, 1H, NH⁺), 9.80 (s, 1H, NH⁺), 11.50 (s, 1H, NH⁺).

IR: ν_(C═O) (urea): 1660 cm⁻¹; ν_(C═N) (amidine): 1640 cm⁻¹.

Example 62

1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (62)

62.11-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(1,1-dimethylethoxy)carbonyl]-aminophenoxy}azetidine

Condensation of 2-hydroxy 5-methoxybenzoic acid and of intermediate 61.4is carried out under the same experimental conditions as those describedfor intermediate 40.1. A white solid is obtained with a yield of 62%.Melting point: 152-153° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 9H, tBu), 3.70 (s, 3H, OCH₃),4.00-4.80 (m, 4H, azetidine), 5.00 (m, 1H, CH—O), 6.70-6.90 (m, 5H,arom. H), 7.30 (m, 2H, arom. H), 9.1 (s, 1H, OH), 10.65 (s, 1H, NH).

62.2 1-(2-hydroxy-5-methoxybenzoyl)-3-aminophenoxy-azetidine

The experimental protocol used is the same as that described forintermediate 58.3, intermediate 62.1 replacing intermediate 58.2. Ayellow oil is obtained with a yield of 90%.

NMR ¹H (DMSO d6, 400 MHz, δ): 3.25 (wide s, 2H, NH₂), 3.80 (s, 3H,OCH₃), 4.20-4.90 (m, 4H, azetidine), 4.95 (m, 1H, CH—O), 6.60-7.00 (m,7H, arom. H), 11.35 (wide s, 1H, OH).

62.31-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (62)

The experimental protocol used is the same as that described forintermediate 36.3, intermediate 62.2 replacing intermediate 36.2. Awhite powder is obtained with a yield of 44%. Melting point: 165-166° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 3.70 (s, 3H, OCH₃), 4.00-4.80 (m, 4H,azetidine), 5.15 (m, 1H, CH—O), 6.80-7.10 (m, 5H. arom. H), 7.40 (m, 3H,arom. H), 8.20 (m, 2H, thiophene), 8.75 (wide s, 1H, NH⁺), 9.80 (wide s,1H, NH⁺), 10.60 (s, 1H, OH), 11.50 (wide s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1655 cm⁻¹; ν_(C═N) (amidine): 1612 cm⁻¹.

Example 63

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidineHydrochloride (63)

63.1 1,1-dimethylethyl 4-(4-nitrophenoxy)-1-piperidinecarboxylate

A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine (prepared ina standard fashion starting from commercial 4-hydroxypiperidine) in 10ml of dry THF is added dropwise to a solution of 1.23 g (11 mmol) oftBuO⁻K⁺ in 10 ml of dry THF in a three necked flask, under an inertatmosphere, cooled by an ice bath. After agitation for 30 minutes at 0°C., a solution of 1.06 ml (10 mmol) of 4-fluoronitrobenzene in 10 ml ofdry THF is added dropwise. The reaction mixture is agitated for 5 hoursat 23° C. and finally poured into 25 ml of a water+ice mixture. Theproduct is extracted using 50 ml of ethyl acetate. After decantation,the organic phase is washed twice with 25 ml of water and 25 ml of saltwater. The organic solution is dried over magnesium sulphate, followedby filtration and concentration of the filtrate under vacuum to producea residue which is purified on a silica column (eluant: heptane/ethylacetate: 8/2). The pure fractions are collected and evaporated undervacuum. The expected product is obtained in the form of a pale yellowpowder with a yield of 47%. Melting point: 97-98° C.

63.2 4-(4-nitrophenoxy)piperidine

The experimental protocol used is the same as that described forintermediate 51.2, intermediate 63.1 replacing intermediate 51.1. Ayellow oil is obtained with a yield of 87%.

NMR ¹H (CDCl₃, 100 MHz, δ): 1.58 (s, 1H, NH), 1.59-2.19 (m, 4H,CH₂—CH₂), 2.65-3.30 (m, 4H, CH₂—CH₂), 4.51 (m, 1H, CH—O), 6.98 (m, 2H,arom. H), 8.21 (m, 2H, arom. H).

63.31-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-(4-nitrophenyl)piperidine

The experimental protocol used is the same as that described forintermediate 51.3, intermediate 63.2 replacing intermediate 51.2. A paleyellow powder is obtained with a crude yield of 83%. The product issufficiently pure to be used directly in the following stage.

63.41-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-(4-aminophenyl)piperidine

The experimental protocol used is similar to that described forintermediate 46.4, intermediate 63.3 replacing intermediate 46.3. Thereaction is carried out in a dichloromethane/ethanol mixture (1/1). Awhite powder is obtained with a yield of 77%. Melting point: 153-154° C.

NMR ¹H (CDCl₃+D₂O, 400 MHz, δ): 1.60-2.18 (m, 18H, CH₂+Trolox),2.52-2.81 (m, 2H, CH₂), 3.41-4.28 (m, 5H, 2×CH₂+CH—O), 6.63 (m, 2H,arom. H), 6.74 (m, 2H, arom. H).

63.51-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}piperidineHydrochloride (63)

The protocol used is the same as that described for intermediate 34.4,intermediate 63.4 replacing intermediate 34.3. The condensation reactionis carried out in 2-propanol only. After salification, the expectedproduct is obtained in the form of a yellow powder with a yield of 25%.Melting point: decomposition from 170° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.50-2.10 (m, 18H, CH₂+Trolox), 2.40-2.65(m, 2H, CH₂), 3.13-4.37 (m, 4H, 2×CH₂), 4.64 (m, 1H, CH—O), 7.11 (m, 2H,arom. H), 7.35 (m, 2H, arom. H), 7.57 (s, 1H, arom. H), 8.17 (m, 2H,arom. H), 8.74 (wide s, 1H, NH⁺), 9.76 (wide s, 1H, NH⁺), 11.42 (wide s,1H, NH⁺).

IR: ν_(C═O) (amidine): 1611 cm⁻¹.

Example 64

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidineHydrochloride (64)

64.11-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(1,1-dimethylethoxy)carbonyl]aminophenoxy}azetidine

The condensation of Trolox and intermediate 51.4 is carried out underthe same experimental conditions as those described for intermediate40.1. A white solid is obtained with a yield of 98%. Melting point:182-183° C.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 9H, tBu), 1.60-2.60 (m, 16H,Trolox), 3.90-4.90 (m, 5H, azetidine), 6.40 (s, 1H, OH), 6.65 (m, 2H,arom. H), 7.20-7.30 (m, 3H, arom. H+NH).

64.21-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-aminophenoxy-azetidine

The experimental protocol used is the same as that described forintermediate 58.3, intermediate 64.1 replacing intermediate 58.2. Awhite foam is obtained with a yield of 43%.

NMR ¹H (CDCl₃, 400 MHz, δ): 1.60-2.60 (m, 16H, Trolox), 3.50 (wide s,2H, NH₂), 3.90-4.90 (m, 5H, azetidine), 6.50-6.70 (m, 4H, arom. H).

64.31-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (64)

The experimental protocol used is the same as that described forintermediate 36.3, intermediate 64.2 replacing intermediate 36.2. Awhite powder is obtained with a yield of 56%. Melting point: 190-195° C.

NMR ¹H (DMSO d6, 400 MHz, δ): 1.60-2.50 (m, 16H, Trolox), 3.60-5.00 (m,5H, azetidine), 6.90 (m, 2H, arom. H), 7.30 (m, 3H, arom. H), 8.15 (m,2H, thiophene), 8.80 (wide s, 1H, NH⁺), 9.80 (wide s, 1H, NH⁺), 11.50(wide s, 1H, NH⁺).

IR: ν_(C═O) (amide): 1647 cm⁻¹; ν_(C═N) (amidine): 1611 cm⁻¹.

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Study of theEffects on Neuronal Constitutive NO Synthase of a Rat's Cerebellum

The inhibitory activity of the products of the invention is determinedby measuring their effects on the conversion by the NO synthase of the[³H]L-arginine in [³H]L-citrulline according to the modified method ofBredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87: 682-685). Thecerebellums of Sprague-Dawley rats (300 g—Charles River) are rapidlyremoved, dissected at 4° C. and homogenized in a volume of extractionbuffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg/ml, leupeptin10 mg/ml). The homogenates are then centrifuged at 21000 g for 15 min at4° C. Dosage is carried out in glass test tubes in which 100 μl ofincubation buffer containing 100 mM of HEPES (pH 7.4), 2 mM of EDTA, 2.5mM of CaCl₂, 2 mM of dithiotreitol, 2 mM of reduced NADPH and 10 μg/mlof calmodulin are distributed. 25 μl of a solution containing 100 nM of[³H]L-arginine (Specific activity: 56.4 Ci/mmole, Amersham) and 40 μM ofnon-radioactive L-arginine is added. The reaction is initiated by adding50 μl of homogenate, the final volume being 200 μl (the missing 25 μlare either water or the tested product). After 15 min, the reaction isstopped with 2 ml of stopping buffer (20 mM of HEPES, pH 5.5, 2 mM ofEDTA). After placing the samples on a 1 ml column of DOWEX resin, theradioactivity is quantified by a liquid scintillation spectrometer. Thecompounds of examples 6, 7, 13, 14, 33 and 38 to 40 described above showan IC₅₀ lower than 3.5 μM. Compound of Example 35 shows an IC₅₀ lowerthan 5 μuM.

Study of the Effects on Lipidic Peroxidation of the Cerebral Cortex of aRat

The inhibitory activity of the products of the invention is determinedby measuring their effects on the degree of lipidic peroxidation,determined by the concentration of malondialdehyde (MDA). The MDAproduced by peroxidation of unsaturated fatty acids is a good indicationof lipidic peroxidation (H Esterbauer and KH Cheeseman, Meth. Enzymol.(1990) 186: 407-421). Male Sprague Dawley rats of 200 to 250 g (CharlesRiver) were sacrificed by decapitation. The cerebral cortex is removed,then homogenized using a Thomas potter in a 20 mM Tris-HCl buffer,pH=7.4. The homogenate was centrifuged twice at 50000 g for 10 minutesat 4° C. The pellet is maintained at −80° C. On the day of theexperiment, the pellet is replaced in suspension at a concentration of 1g/15 ml and centrifuged at 515 g for 10 minutes at 4° C. The supernatantis used immediately to determine the lipidic peroxidation. Thehomogenate of rat's cerebral cortex (500 μl) is incubated at 37° C. for15 minutes in the presence of the compounds to be tested or of solvent(10 μl). The lipidic peroxidation reaction is initiated by adding 50 μIof FeCl₂ at 1 mM, EDTA at 1 mM and ascorbic acid at 4 mM. After 30minutes of incubation at 37° C., the reaction is stopped by adding 50 μlof a solution of hydroxylated di tertio butyl toluene (BHT, 0.2%). TheMDA is quantified using a colorimetric test, by reacting a chromogenicreagent (R), N-methyl-2-phenylindol (650 μl) with 200 μl of thehomogenate for 1 hour at 45° C. The condensation of an MDA molecule withtwo molecules of reagent R produce a stable chromophore the maximumabsorbence wavelength of which is equal to 586 nm. (Caldwell et al.European J. Pharmacol. (1995) 285, 203-206). The compounds of Examples5, 8 to 10, 12 to 14, 16 to 21, 26, 27, 35 and 43 to 47 described aboveall show an IC₅₀ lower than 30 μM.

What is claimed is:
 1. A compound selected from the group consisting ofa compound of the formula

wherein A is selected from the group consisting of hydrogen,

R₁ and R₂ are individually selected from the group consisting ofhydrogen, halogen, —OH, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to6 carbon atoms, R₃ is selected from the group consisting of hydrogen,alkyl of 1 to 6 carbon atoms and —COR₄, R₄ is alkyl of 1 to 6 carbonatoms, R₅ is selected from the group consisting of hydrogen, —OH, alkylof 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms, B is selectedfrom the group consisting of alkyl of 1 to 6 carbon atoms andcarbocyclic aryl and heterocyclic aryl of 5 to 6 ring members containingin the ring 1 to 4 heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur with the aryl unsubstituted or substitutedwith at least one member of the group consisting of alkyl, alkenyl andalkoxy of up to 6 carbon atoms, X is selected from the group consistingof a single bond, —Z₁—, —Z₁CO—, —CH═, —CH═CH—CO—, —Z₁—NR₃—CO—Z′₁—,—CONR₃—Z′₁—, —Z₁—NR₃—CS— and —Z₁—NR₃—SO₂—, Het is a heterocycle selectedfrom the group consisting of oxetane, pyrrole, pyrrolidine, furan,tetrahydrofuran, thiophene, tetrahydrothiophene, sulpholane, imidazole,imidazoline, dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole,isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoine, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine and4-aminopiperidine, Y is selected from the group consisting of Z₂—Q—,—Z₂CO—, —Z₂—NH—CO—, —Z₂—CH₂—NR₃—CO—, —NR₃—Z₂—Q—, —NR₃—CO—Z₂—Q—,—NR₃—NH—CO—Z₂—, —NH—NH—Z₂—, —NR₃—O—Z₂—, —NR₃—SO₂—NR₃—Z₂—, —O—Z₂—Q—,—O—CO—Z₂—Q— and —S—Z₂—Q—, Q is selected from the group consisting of—O—Z₃, —R₃—N—Z₃ and —S—Z₃, Z₁, Z′₁, Z₂ and Z₃ are individually selectedfrom the group consisting of a single bond and alkylene of 1 to 6 carbonatoms, R₆ is hydrogen or —OH with the proviso that when A is hydrogen,Het is not piperidine or pyrrolidino or morpholino and its non-toxic,pharmaceutically acceptable salts.
 2. A compound of claim 1 wherein A is

wherein R₁ and R₂ are individually branched alkyl of 3 to 6 carbon atomsand R₃ and R₄ are defined as in claim
 1. 3. A compound of claim 1wherein B is

wherein R₃ is defined as in claim 1 and its pharmaceutically acceptablesalts.
 4. A compound of claim 3 which is(S)-N-{4-[4-[3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide and its pharmaceutically acceptable salts.
 5. A compoundof claim 1 selected from the group consisting ofN-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide;N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;N-[4-(1H-imidazol-1-yl methyl]-2-thiophenecarboximidamide;N-[4-{2-(3-thiazolidinyl)ethyl}phenyl-[-2-thiophenecarboximidamide;N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;N-{4-[2-(1,2,3,6-tetrahydropropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide;N-(3,5di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)methylamino}phenyl]-2-furancarboxamide;3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)methylamino}phenyl]2,5-imidazolidinedione;2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)methylamino}phenyl]-4-thiazolidinone;5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione;2-(S)-4-(S)-N-[4-hydroxy-3,5-bis(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thenyl)methyl)amino]phenoxy}-prolinamide;5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridinecarboxamide;N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(RS)-{4-(imino(2-thienyl)methyl)amino)phenyl}-4-(R)-thiazolidinecarboxamide;N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamide;N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamide;methyll-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)amino]phenoxy}-pyrrolidine-2-(S)-carboxylate;1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine;3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-]1[benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl]pyrrolidine;4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-(imino(2-thienyl)methyl)amino]benzoyl]}-N-methyl-1H-imidazole-2-methanamine;N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-[1H]-pyrrole-2-carboxamide;1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[(imino(2-thienyl)methyl]amino)phenyl]carbonyl}-2-imidazolidinone;3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamide;4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamine;4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamine;3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino[phenoxy}ethyl}isoxazole;1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}carbonyl}-3-{4-[imino(2-thienyl)methyl)amino]phenoxy}azetidine;1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidine;1-[3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidine;or its non-toxic pharmaceutically acceptable salts.
 6. A compoundaccording to claim 5, characterized in that it is one of the followingcompounds:-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;-N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;-(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;-(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;-N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.
 7. Acompound of claim 1 the formula

wherein A, Z₁, Z₂, Z₃, Q, R₁, R₂, R₃, R₄, R₅, B and R₆ are defined as inclaim 1, X is selected from the group consisting of —Z₁—, —Z₁—CO—,—CH═CH—CO—, —Z₁NR₃—CO—, —Z₁—NR₃—CS, —Z₁—NR₃—SO₂— and a single bond, Y isselected from the group consisting of piperazine, homopiperazine,2-methyl-piperazine, 2,5-dimethylpiperazine and 4-amino-piperidine andits pharmaceutically acceptable salts.
 8. A compound of claim 7 whereinA is

wherein X is —CO— or —NH—CO— and Y is piperazine and R₃ is hydrogen oralkyl of 1 to 6 carbon atoms and its pharmaceutically acceptable salts.9. A compound of claim 1 of the formula

wherein A is selected from the group consisting of hydrogen,

R₁, R₂, R₃, R₄, Het and B are defined as in claim 1, X is selected fromthe group consisting of —CO—NR₃—X′, —NH—CO—X′, —CH═, —CO— and a bond, X′is —(CH₂)_(m)—, m is an integer from 0 to 6, Y is selected from thegroup consisting of —Y′—, —CO—NH—Y′—, —Y′—NH—CO—, —COY′—, —Y′—CO—,—NR₃—Y′—, —Y′—NR₃—, —Y′—CH₂—NR₃—CO—, —OY′—, —Y′—O—, —S—Y′—, —Y′—S—,—Y′—O—Y′—, —Y′—NR₃—Y′— and a bond, Y′ is —(CH₂)_(n)—, n is an integerfrom 0 to 6 with the proviso that when A is hydrogen, Het is notpiperidino or pyrrolidino or morpholino and its pharmaceuticallyacceptable salts.
 10. A compound according to claim 1 characterized inthat it is one of the following compounds:-N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide;-N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;-N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;-N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamide;-N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;-N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;-N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;-N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;-N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide;-N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furancarboxamide;-3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedione;-2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinone;-5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione;-2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamide;-5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridinecarboxamide;-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidinecarboxamide;-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl4-thiazolecarboxamide;-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamide;-methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylate;-1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine;-3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine;-4-[3,5,bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamine;-N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamide;-1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinone;-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamide;-4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamine;-4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamine;-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole;-1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;-1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;-1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidine;-1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidine;or a salt of one of the latter, in particular of a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.
 11. Amethod of inhibiting in a warm-blooded animal comprising administeringto said warm-blooded animal a compound according to claim 1, or of apharmaceutically acceptable salt of this compound, in an amountsufficient to inhibit cerebrovascular or cardiovascular diseasesneuronal NO synthase.
 12. A method of inhibiting and lipidicperoxidation in a warm-blooded animal comprising administering to saidwarm-blooded animal a compound according to claim 1, or of apharmaceutically acceptable salt of this compound, in an amountsufficient to inhibit lipidic peroxidation.
 13. A method of treatingstroke in a warm-blooded animal comprising administering to saidwarm-blooded animal a compound according to claim 1, or of apharmaceutically acceptable salt of this compound, in an amountsufficient to inhibit stroke or neurodegenerative diseases.
 14. A methodof treating stroke according to claim 13, characterized in that thecompound administered is(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide,or a pharmaceutically acceptable salt thereof.
 15. A method of treatingischemic or hemorragic cardiac or cerebral infarctions related withcomplications of coronary artery bypass grafting in a warm-bloodedanimal comprising administering to said warm-blooded animal a compoundaccording to claim 1, or of a pharmaceutically acceptable salt of thiscompound, in an amount sufficient to inhibit said ischemic or hemorragiccardiac or cerebral infarctions.
 16. A method of treating ischemic orhemorragic cardiac or cerebral infarctions related with complications ofcoronary artery bypass grafting according to claim 15, characterized inthat the compound administered is(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide,or a pharmaceutically acceptable salt thereof.